Phenoxy-pyridyl-pyrimidine compounds and methods of use

ABSTRACT

Described herein are phenoxy-pyridyl-pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I structure or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to ChineseInternational Application Serial No. PCT/CN2018/105183, filed Sep. 12,2018, hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The kinase/endoribonuclease inositol requiring enzyme 1 (IRE1α), one ofthe key sensors of misfolded protein accumulation in the endoplasmicreticulum that triggers the unfolded protein response (UPR), is apotential therapeutic target for diverse diseases including cancer forinhibitors that bind to the ATP-binding site on the kinase moiety ofIRE1α and block its endoribonuclease activity. IRE1α is a transmembrane,bifunctional protein with a luminal domain that binds to misfoldedproteins, a transmembrane segment, and a cytoplasmic portion consistingof a kinase moiety and a tandem endoribonuclease domain.Structure-activity relationship (SAR) studies led to compounds selectivein recombinant IRE1α kinase screens and potent against endoribonucleaseactivity of recombinant IRE1α as well as cellular IRE1α. IRE1α activitymediates certain cytoprotective and pro-survival functions of the UPR,increases viability and growth in certain tumor cell lines, and can bean effective therapeutic target for specific small molecule inhibitorsthat block malignant tumor growth, contrary to an earlier report(Harrington, P. E. et al (2015) ACS Med. Chem. Lett. 6:68-72). Inaddition, inhibitors of IRE1α can be therapeutically useful for othertypes of diseases besides cancer including certain autoimmune,neurodegenerative, fibrotic and metabolic disorders (Wang M. andKaufman, R. J. (2016) Nature 529:326-335).

Homeostatic regulation of protein folding in the endoplasmic reticulum(ER) is under the control of three key intracellular signaling pathways:IRE1α, PERK, and ATF6, which together orchestrate the unfolded proteinresponse (UPR) (Schroder, et al (2005) Mutat Res-Fund Mol MechMetagenesis 569:29-63). An increase in demand for protein folding in theER or certain types of cellular injury or stress lead to theaccumulation of unfolded proteins in the ER—a condition called ERstress. Cells respond to ER stress by activating the UPR to help adjustor maintain their high-fidelity protein synthetic capacity (Walter, P.and Ron, D. (2011) Science, 334:1081-1086). IRE1α is the mostevolutionarily conserved of the three branches of the UPR. Importantly,the UPR makes life/death decisions for the cell, depending on theseverity and duration of ER stress, and the final outcome is either cellsurvival and recovery or programmed cell death (apoptosis) (Sovolyova etal, (2014) Biol Chem 395: 1-13). All three pathways of the UPR form acoordinated reaction to the accumulation of unfolded proteins; andseveral studies have demonstrated that there is cross talk between thedifferent pathways (Yamamoto et al, J. Biochem (2004) 136:343-350); Araiet al, FEBS Letts. (2006) 580:184-190; Adachi et al, Cell Struct. Func.(2008) 33:75-89). ER stress and activation of the UPR can be caused bymechanical injury, inflammation, genetic mutations, infections,oxidative stress, metabolic stress, and other types of cellular stressassociated with malignancy. ER stress has also been implicated indiseases that result in flbrotic remodeling of internal organs, such aschronic liver diseases (Galligan et al, J. Toxicol. (2012) Vol. 2012,Article ID 207594, 12 pgs.; Shin et al, Cell Reports (2013) 5:654-665;Ji, Int J. Hepatol. (2014) Vol. 2014, Article ID 513787, 11 pages),pulmonary fibrosis (Baek et al, Am. J. Resp. Cell Mol. Bio. (2012)46:731-739); Tanjore et al, Biochim Biophys Acta (2012, online), (2013)1832:940-947), kidney fibrosis (Chiang et al, Mol. Med. (2011)17:1295-1305), cardiovascular disease (Spitler & Webb, Hypertension(2014) 63:e40-e45), and inflammatory bowel disease (Bogaert et al, PLoSOne (2011) 6(10) e25589; Cao et al, Gastroent (2013) 144:989-1000).

IRE1α is a transmembrane, bifunctional protein with cytoplasmic kinaseand endoribonuclease activity. The N-terminal domain of IRE1α isproposed to sense the presence of unfolded proteins in the ER lumen,triggering activation of the cytoplasmic kinase domain, which, in turn,activates the C-terminal endoribonuclease. IRE1α transmits informationacross the ER lipid bilayer (Tirasophon et al, Genes & Develop. (2000)14:2725-2736). Increased ER protein load and presence of unfoldedproteins leads to the dissociation of the ER chaperone GRP78/BiP fromIRE1α molecules, which bind to misfolded proteins and then undergodimerization and trans-autophosphorylation in the cytoplasmic kinasedomain. This leads to activation of the IRE1α endoribonuclease moiety inthe cytosol. The IRE1α endoribonuclease has the ability to cleave themRNA that encodes unspliced X box protein 1 (XBPlu); this excises a26-nucleotide intron and leads to formation of spliced XBP1 (XBP1s)mRNA, which encodes a potent transcription factor. After transport intothe nucleus, the XBP1s protein binds to UPR promoter elements toinitiate transcription of genes that enhance the ability of the ER tocope with unfolded proteins, for example, through enhanced ER-associateddegradation of misfolded proteins, and through elevated levels ofchaperones and disulfide isomerases that support protein folding in theER. IRE1α activation is also associated with enlargement of the ERvolume, which has been interpreted as an adaptive mechanism to increaseprotein folding capacity (Sriburi et al, J. Cell. Bio. (2004)167:35-41); (Chen, Y. (2013) Trends Cell Biol., 23,547-555). Inaddition, the IRE1α endoribonuclease cleaves various mRNAs in a processcalled regulated IRE1α-dependent decay of mRNA (RIDD), which reducesboth protein translation and import of proteins into the ER to helpreestablish homeostasis (Hollien & Weissman, Science (2006)313:104-107). In cancer cells, IRE1α suppresses ER-stress-inducedapoptosis by reducing the mRNA levels of death receptor 5 (DR5) throughRIDD (Lu et al., Science (2014) 345:98-101).

Besides degrading mRNA (Binet et al, Cell Metabol. (2013) 17:353-371),it was recently shown that IRE1α also has the ability to degrademicroRNAs (miRs) (Upton et al, Science (2012) 338:818-822). miRs areshort noncoding RNA oligonucleotides consisting of 17-25 nucleotidesthat generally act to inhibit gene expression by binding tocomplementary sequences in the 30-untranslated region of target mRNAs,either to repress mRNA translation or to induce mRNA cleavage. A numberof cellular functions such as proliferation, differentiation, andapoptosis are regulated by miRs, and aberrant miR expression is observedin a variety of human diseases including fibrosis (Bowen et al, J.Pathol (2013) 229:274-285). Inhibitors that specifically targetindividual components of the UPR have recently been described. Theinhibitor 4μ8C that stably binds to lysine 907 in the IRE1αendoribonuclease domain has been shown to inhibit both RIDD activity andXBP-1 splicing (Cross et al, Proc Natl. Acad. Sci. (2012)109:E869-E878). High levels of 4 μ8C cause no measurable toxicity incells and concentrations ranging from 80 to 1281M of 4μ8C completelyblock XBP1 splicing without affecting IRE1α (alpha) kinase activity(Cross et al, 2012). The inhibitor 4μ8C thus represents an importanttool to delineate the functions of IRE1α in vivo as IRE1α-knockout micedie during embryonic development. Inhibition of IRE1α preventsactivation of myofibroblasts and reduces fibrosis in animal models ofliver and skin fibrosis. Pharmacological inhibition of IRE1α couldrevert the profibrotic phenotype of activated myofibroblasts isolatedfrom patients with scleroderma and indicates that ER stress inhibitorsshould be taken into consideration when developing new strategies forthe treatment of fibrotic diseases (Heindryckx, F. et al (2016) EMBOMolecular Medicine Vol 8(7): 729-744).

Activation of the UPR has been shown to be an important survival pathwayfor tumors of secretory cell origin like multiple myeloma that have avery high protein synthesis burden. Therefore, efforts to disrupt theUPR by blocking the IRE1α endoribonuclease cleavage and activation ofXBP1 have been an active area of cancer research. As a specific IRE1αRNase product, XBP1s is a direct indicator of functional IRE1inhibition. A potent and selective IRE1α inhibitor would serve as animportant tool to test the hypothesis that, without full UPR activation,tumor cells would be driven to apoptosis. IRE1α inhibitors andactivating compounds have been reported (Harrington, P. E. et al (2015)ACS Med. Chem. Lett. 6:68-72; Volkmann, K., et al (2011) J. Biol. Chem,286:12743-12755; Cross, B. C. S., et al (2012) Proc. Natl. Acad. Sci.U.S.A., 109E869-E878; Wang, L., et al (2012) Nat. Chem Biol., 8:982-989;Ghosh, R., et al (2014) Cell, 158:534-548; Ranatunga, S., et al (2014)J. Med. Chem, 57, 4289-4301; U.S. Pat. Nos. 9,382,230; 8,815,885).

There remains a need for potent and selective inhibitors having suitablepharmacological properties for the treatment of IRE1-related diseases ordisorders in patients.

BRIEF SUMMARY OF THE INVENTION

Disclosed are phenoxy-pyridyl-pyrimidine compounds that target IRE1α,compositions containing these compounds, and methods for the treatmentof IRE1-related diseases or disorders.

In one aspect, provided is a compound of Formula (I), or apharmaceutically acceptable salt thereof as detailed herein. Alsoprovided is a pharmaceutical composition comprising a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable excipients.

In another aspect, provided is a method for treating an IRE1-relateddisease or disorder in a subject in need thereof comprisingadministering to the subject an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof. In someembodiments, the subject is a human. In some embodiments, theIRE1-related disease or disorder is a cancer. In some embodiments, themethod further comprises administering an anti-cancer agent to thesubject.

Also provided is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof for use in a method of treating an IRE1-relateddisease or disorder.

Still further provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof for use in a method of treatingcancer.

Also provided is use of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, in a method detailed herein (e.g., treatment ofan IRE1-related disease or disorder).

Also provided is use of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for use ina method detailed herein (e.g., treatment of an IRE1-related disease ordisorder).

Also provided is a kit for treating an IRE1-related disease or disorder,the kit comprising a pharmaceutical composition comprising a compound ofFormula (I) or a pharmaceutically acceptable salt thereof; andinstructions for use.

In still another aspect provided herein is a method of inhibiting orkilling a cancer cell expressing Ire1, where the method comprisescontacting the cancer cell expressing Ire1 with a compound orpharmaceutically acceptable salt thereof described herein.

In yet another aspect provided herein is a method of modulating Ire1activity, where the method comprises contacting Ire1 with a compound orpharmaceutically acceptable salt thereof described herein.

Also provided is a kit for treating cancer, where the kit comprises apharmaceutical composition comprising a the compound described herein,or a pharmaceutically acceptable salt thereof; and instructions for use.

In another aspect provided herein is a method of making a compound ofFormula (I). Also provided are compound intermediates useful insynthesis of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof described herein.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein, are phenoxy-pyridyl-pyrimidine compounds of Formula(I), including pharmaceutically acceptable salts thereof andpharmaceutical compositions thereof that are inhibitors or modulators ofIRE1α. As such, the compounds and compositions are useful in treatingdiseases and disorders mediated by IRE1α.

While the disclosure herein provides enumerated embodiments, it will beunderstood that they are not intended to limit the invention to thoseembodiments. On the contrary, the disclosure is intended to cover allalternatives, modifications, and equivalents which can be includedwithin the scope of the present invention as defined by the claims. Oneskilled in the art will recognize many methods and materials similar orequivalent to those described herein. The present invention is in no wavlimited to the methods and materials described. In the event that one ormore of the incorporated literature, patents, and similar materialsdiffers from or contradicts this application, including but not limitedto defined terms, term usage, described techniques, or the like, thisapplication controls. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the methodsand materials are described below. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. The nomenclature used inthis Application is based on IUPAC systematic nomenclature, unlessindicated otherwise.

Definitions

“Alkyl” as used herein refers to a saturated linear (i.e. unbranched) orbranched univalent hydrocarbon chain or combination thereof, having thenumber of carbon atoms designated (i.e., C₁₋₁₀ means one to ten carbonatoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a“C₁₋₂₀ alkyl”), having a 1 to 8 carbon atoms (a “C₁₋₈ alkyl”), having 1to 6 carbon atoms (a “C₁₋₆ alkyl”), having 2 to 6 carbon atoms (a “C₂₋₆alkyl”), or having 1 to 4 carbon atoms (a “C₁₋₄ alkyl”). Examples ofalkyl group include, but are not limited to, groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like.

“Alkenyl” as used herein refers to an unsaturated linear (i.e.,unbranched) or branched univalent hydrocarbon chain or combinationthereof, having at least one site of olefinic unsaturation (i.e., havingat least one moiety of the formula C═C) and having the number of carbonatoms designated (i.e., C₂₋₁₀ means two to ten carbon atoms). Thealkenyl group can be in “cis” or “trans” configurations, oralternatively in “E” or “Z” configurations. Particular alkenyl groupsare those having 2 to 20 carbon atoms (a “C₂₋₂₀ alkenyl”), having a 2 to8 carbon atoms (a “C₂₋₈ alkenyl”), having 2 to 6 carbon atoms (a “C₂₋₆alkenyl”), or having 2 to 4 carbon atoms (a “C₂₋₄ alkenyl”). Example ofalkenyl group include, but are not limited to, groups such as ethenyl(or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl,but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl,2-methylbuta-1,3-dienyl, homologs and isomers thereof, and the like.

“Alkynyl” as used herein refers to an unsaturated linear (i.e.unbranched) or branched univalent hydrocarbon chain or combinationthereof, having at least one site of acetylenic unsaturation (i.e.,having at least one moiety of the formula C≡C) having the number ofcarbon atoms designated (i.e., C₂₋₁₀ means two to ten carbon atoms).Particular alkynyl groups are those having 2 to 20 carbon atoms (a“C₂₋₂₀ alkynyl”), having a 2 to 8 carbon atoms (a “C₂₋₈ alkynyl”),having 2 to 6 carbon atoms (a “C₂₋₆ alkynyl”), having 2 to 4 carbonatoms (a “C₂₋₄ alkynyl”). Examples of alkynyl group include, but are notlimited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl,prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologsand isomers thereof, and the like.

“Alkylene” as used herein refers to the same residues as alkyl, buthaving bivalency. Particular alkylene groups are those having 1 to 6carbon atoms (a “C₁₋₆ alkylene”), 1 to 5 carbon atoms (a “C₁₋₅alkylene”), having 1 to 4 carbon atoms (a “C₁₋₄ alkylene”), or 1 to 3carbon atoms (a “C₁₋₃ alkylene”). Examples of alkylene include, but arenot limited to, groups such as methylene (—CH₂—), ethylene (—CH₂—CH₂—),propylene (—CH₂—CH₂—CH₂—), butylene (—CH₂—CH₂—CH₂—CH₂—), and the like.

“Cycloalkyl” as used herein refers to non-aromatic, saturated orunsaturated cyclic univalent hydrocarbon structures having the number ofcarbon atoms designated (i.e., (C₃₋₁₀ means three to ten carbon atoms).Cycloalkyl can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantly, but excludes aryl groups. A cycloalkylcomprising more than one ring can be fused, spiro, or bridged, orcombinations thereof. Particular cycloalkyl groups are those having from3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃₋₈cycloalkyl”), or having 3 to 6 carbon atoms (a “C₃₋₆ cycloalkyl”).Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohyxyl, 1-cyclohexenyl, 3-cyclohexenyl,cycloheptyl, norbomyl, and the like.

“Aryl” as used herein refers to an unsaturated aromatic carbocyclicgroup having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl) which condensed rings can or can not bearomatic. Particular aryl groups are those having from 6 to 14 annular(i.e., ring) carbon atoms (a “C₆₋₁₄ aryl”). An aryl group having morethan one ring where at least one ring is non-aromatic can be connectedto the parent structure at either an aromatic ring position or at anon-aromatic ring position. In one variation, an aryl group having morethan one ring where at least one ring is non-aromatic is connected tothe parent structure at an aromatic ring position.

“Heteroaryl” as used herein refers to an unsaturated aromatic cyclicgroup having from 1 to 14 annular (i.e., ring) carbon atoms and at leastone annular heteroatom, including but not limited to heteroatoms such asnitrogen, phosphorus, oxygen and sulfur. A heteroaryl group can have asingle ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g.,indolizinyl, benzothienyl) which condensed rings can or can not bearomatic. Particular heteroaryl groups are 5- to 14-membered ringshaving 1 to 12 annular (i.e., ring) carbon atoms and 1 to 6 annular(i.e., ring) heteroatoms independently selected from nitrogen,phosphorus, oxygen and sulfur; 5- to 10-membered rings having 1 to 8annular carbon atoms and 1 to 4 annular heteroatoms independentlyselected from nitrogen, phosphorus, oxygen and sulfur; and 5-, 6- or7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annularheteroatoms independently selected from nitrogen, oxygen and sulfur Inone variation, heteroaryl include monocyclic aromatic 5-, 6- or7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4annular heteroatoms independently selected from nitrogen, oxygen andsulfur. In another variation, heteroaryl includes polycyclic aromaticrings having from 1 to 12 annular carbon atoms and 1 to 6 annularheteroatoms independently selected from nitrogen, phosphorus, oxygen andsulfur. A heteroaryl group having more than one ring where at least onering is non-aromatic can be connected to the parent structure at eitheran aromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refersto a saturated or an unsaturated non-aromatic cyclic group having asingle ring or multiple condensed rings, and having from 1 to 14 annular(i.e., ring) carbon atoms and from 1 to 6 annular (i.e., ring)heteroatoms, such as nitrogen, phosphorus, sulfur or oxygen, and thelike. A heterocycle comprising more than one ring can be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or morecan be fused rings can be cycloalkyl. Particular heterocyclyl groups are3- to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6annular heteroatoms independently selected from nitrogen, phosphorus,oxygen and sulfur; 3- to 12-membered rings having 1 to 11 annular carbonatoms and 1 to 6 annular heteroatoms independently selected fromnitrogen, phosphorus, oxygen and sulfur; 3- to 10-membered rings having1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independentlyselected from nitrogen, phosphorus, oxygen and sulfur; 3- to 8-memberedrings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatomsindependently selected from nitrogen, phosphorus, oxygen and sulfur; and3- to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4annular heteroatoms independently selected from nitrogen, phosphorus,oxygen and sulfur. In one variation, heterocyclyl include monocyclic 3-,4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to5 or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3 or 1 to 4 annularheteroatoms independently selected from nitrogen, phosphorus, oxygen andsulfur. In another variation, heterocyclyl includes polycyclicnon-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6annular heteroatoms independently selected from nitrogen, phosphorus,oxygen and sulfur.

“Halo” or Halogen” refers to fluoro, chloro, bromo and/or iodo. Where aresidue is substituted with more than one halogen, it can be referred toby using a prefix corresponding to the number of halogen moietiesattached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryland alkyl substituted with two (“di”) or three (“tri”) halo groups,which can be but are not necessarily the same halo; thus4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkylgroup in which one or more hydrogen is replaced with a halo group isreferred to as a “haloalkyl”, for example, “C₁₋₆ haloalkyl.” An alkylgroup in which each hydrogen is replaced with a halo group is referredto as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl(—CF₃). Similarly, “perhaloalkoxy” refers to an alkoxy group in which ahalogen takes the place of each H in the hydrocarbon making up the alkylmoiety of the alkoxy group. An example of a perhaloalkoxy group istrifluoromethoxy (—OCF₃).

“Carbonyl” refers to the group C═O.

“Thiocarbonyl” refers to the group C═S.

“Oxo” refers to the moiety ═O.

The terms “treat” and “treatment” refer to therapeutic treatment,wherein the object is to slow down (lessen) an undesired physiologicalchange or disorder, such as the development or spread of arthritis orcancer. Beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms, diminishment of extent of disease,stabilized (i.e., not worsening) state of disease, delay or slowing ofdisease progression, amelioration or palliation of the disease state,and remission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those with the condition or disorder.

The phrase “effective amount” means an amount of a compound orpharmaceutically acceptable salt thereof that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein or(iv) favorably alters the clinical response of a patient to thetreatment, where the inhibition and favorability is relative to acontrol (e.g. non-treatment or prior treatment with an anti-cancer agentsuch as that described herein). In the case of cancer, the effectiveamount of the drug can reduce the number of cancer cells; reduce thetumor size; inhibit (i.e., slow to some extent and preferably stop)cancer cell infiltration into peripheral organs; inhibit (i.e., slow tosome extent and preferably stop) tumor metastasis; inhibit, to someextent, tumor growth; and/or relieve to some extent one or more of thesymptoms associated with the cancer. To the extent the drug can preventgrowth and/or kill existing cancer cells, it can be cytostatic and/orcytotoxic. For cancer therapy, efficacy can be measured, for example, byassessing the time to disease progression (TTP) and/or determining theresponse rate (RR).

The term “clinical response” refers to inhibition of diseaseprogression, inhibition of tumor growth, reduction of primary tumor,relief of tumor-related symptoms, inhibition of tumor secreted factors(including tumor secreted hormones, such as those that contribute tocarcinoid syndrome), delayed appearance of primary or secondary tumors,slowed development of primary or secondary tumors, decreased occurrenceof primary or secondary-tumors, slowed or decreased severity ofsecondary effects of disease, arrested tumor growth and regression oftumors, increased Time To Progression (TTP), increased Progression FreeSurvival (PFS), increased Overall Survival (OS), among others. OS asused herein means the time from treatment onset until death from anycause. In general, clinical response refers to primary or secondarymeasures of efficacy known and understood in the art. Treatment andclinical response as described herein can be assessed usinginternational standards for a given condition.

The term “Time To Progression” or “TTP” as used herein refers to thetime from treatment onset until tumor progression.

The term “Progression Free Survival” or “PFS” refers to the time fromtreatment onset until tumor progression or death. In one embodiment, PFSrates can be computed using the Kaplan-Meier estimates.

The clinical response of a patient described herein can be characterizedas a complete or partial response. “Complete response” (CR) refers to anabsence of clinically detectable cancer with normalization of anypreviously abnormal radiographic studies, bone marrow, and cerebrospinalfluid (CSF) or abnormal monoclonal protein measurements. “Partialresponse” (PR) refers to at least about a 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, or 90% decrease in all measurable cancer burden (i.e., thenumber of malignant cells present in the subject, or the measured bulkof tumor masses or the quantity of abnormal monoclonal protein). Theterm “treatment” includes both a complete and a partial response.

The terms “patient” and “subject” are used interchangeably herein andrefer to an animal, including, but not limited to, an animal such a cow,monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,rabbit or guinea pig, in one embodiment a mammal, in another embodimenta human. In one embodiment, a subject is a human having or at risk forhaving cancer, in particular, a cancer described herein. In oneembodiment, a patient is a human having histologically orcytologically-confirmed cancer, including subjects who have progressedCHI (or not been able to tolerate) standard anticancer therapy or forwhom no standard anti cancer therapy exists.

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), small-cell lung cancer, non-small cell lungcancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer,peritoneum cancer, hepatocellular cancer, stomach cancer,gastrointestinal cancer, esophageal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial cancer, uterine cancer, salivary gland carcinoma, renalcancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellularcarcinoma (HCC), anal carcinoma, penile carcinoma, or head and neckcancer.

“Hematological malignancies” (British spelling “Haematological”malignancies) are the types of cancer that affect blood, bone marrow,and lymph nodes. As the three are intimately connected through theimmune system, a disease affecting one of the three will often affectthe others as well: although lymphoma is a disease of the lymph nodes,it often spreads to the bone marrow, affecting the blood. Hematologicalmalignancies are malignant neoplasms (i.e. cancer), and they aregenerally treated by specialists in hematology and/or oncology.Hematological malignancies can derive from either of the two major bloodcell lineages: myeloid and lymphoid cell lines. Lymphomas, lymphocyticleukemias, and myeloma are from the lymphoid line, while acute andchronic myelogenous leukemia, myelodysplastic syndromes andmyeloproliferative diseases are myeloid in origin. Exemplary leukemiasinclude acute lymphoblastic leukemia (ALL), acute myelogenous leukemia(AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia(CML), acute monocytic leukemia (AMOL) and small lymphocytic lymphoma(SLL). Exemplary lymphomas include Hodgkin's lymphomas (all foursubtypes) and Non-Hodgkin's lymphomas (NHL, all subtypes).

A “anti-cancer agent” is a chemical compound useful in the treatment ofcancer, regardless of mechanism of action. Classes of anti-cancer agentsinclude, but are not limited to: alkylating agents, antimetabolites,anti-hormone therapies, endocrine therapies, immunomodulatory agents,spindle poison plant alkaloids, cytotoxic/antitumor antibiotics,topoisomerase inhibitors, antibodies, photosensitizers, and kinaseinhibitors. Anti-cancer agents include compounds used in targetedtherapy and conventional chemotherapy.

Exemplary anti-cancer agents include proteasome inhibitors such asbortezomib (VELCADE), carfilzomib (KYPROLIS) and ixazomib (NINLARO).Other examples include immunomodulatory agents such as lenalidomide(REVLIMID) and pomalidomide (POMALYST).

Other exemplary anti-cancer agents include inhibitors of B-cell receptortargets such as BTK, Bcl-2 and JAK inhibitors and include, for example,venetoclax (VENCLEXTA) and ibrutinib (IMBRUVICA).

Additional anti-cancer agents include, for example, Abemaciclib(VERZENIO); abiraterone (ZYTIGA, YONSA); aclarubicin; acivicin;acodazole; acronine; actinomycin; acylfulvene; adecypenol; adozelesin;adriamycin; aldesleukin; altretamine; ambamustine; ambomycin;ametantrone; amidox; amifostine; aminoglutethimide; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;antarelix; anthramycin; aphidicolin glycinate; apurinic acid; ARRY-300;arabinoside; asperlin; asulacrine; atamestane; atrimustine; azasetron;azatoxin; azatyrosine; azacitidine; AZD6244; AZD8330; azetepa;azotomycin; balanol; batimastat; bendamustine; benzochlorins; benzodopa;benzoylstaurosporine; beta-alethine; betaclamycin B; betulinic acid;bicalutamide; binimetinib; bisantrene; bisaziridinylspermine; bisnafide;bistratene; bleomycin; busulfan; bizelesin; breflate; bortezomib;brequinar; bropirimine; budotitane; buthionine; bryostatin;cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin;capecitabine (XELODA); caracemide; carbetimer; carboplatin; carboquone;carmustine; carubicin; carzelesin; castanospermine; celecoxib;cetrorelix; cetuximab (ERBITUX); chloroquinoxaline; cicaprost;chlorambucil; chlorofusin; cisplatin; cladribine; clomifene;clotrimazole; crisnatol; crisnatol; cypemycin; cyclophosphamide;cytarabine; cytostatin; dacarbazine; dactinomycin; daratumamab;daunorubicin; decarbazine; dacliximab; dasatinib; decitabine;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;dexormaplatin; dezaguanine; diaziquone; dihydrotaxol; docosanol;dolasetron; docetaxel; doxorubicin; doxifluridine; droloxifene;dromostanolone; dronabinol; duazomycin; ebselen; ecomustine; edelfosine;edrecolomab; edatrexate; eflomithine; elemene; emitefur; elsamitrucin;enloplatin; enpromate; epipropidine; epirubicin; epristeride;erbulozole; erlotinib (TARCEVA); esorubicin; estramustine; etanidazole;etoposide; etoprine; exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;floxuridine; fludarabine; fludarabine; fluorodaunorubicin; forfenimex;formestane; fluorouracil; floxouridine; flurocitabine; fosquidone;fostriecin; fotemustine; fulvestrant (FASLODEX); gadolinium; gallium;galocitabine; ganirelix; gemcitabine; geldanamycin; gefitinib;gossyphol; hydroxyurea; hepsulfam; heregulin; ibandronate; ibrutinib;idarubicin; idelalisib (ZYDELIG), ifosfamide; canfosfamide; ilmofosine;iproplatin; idoxifene; idramantone; ilmofosine; ilomastat; imatinibmesylate (GLEEVEC); imiquimod; iobenguane; iododoxorubicin; ipomeanol;irinotecan; itasetron; iimofosine; lanreotide; lapatinib (TYKERB);leinamycin; lenograstim; lentinan; leptolstatin; letrozole; leuprorelin;levamisole; liarozole; lobaplatin; lombricine; lometrexol; lonidamine;lonafamib (SARASAR); losoxantrone; lovastatin; loxoribine; lurtotecan;lapatinib; leucovorin; lometrexol; lomustine; maitansine; marimastat;masoprocol; maspin; menogaril; merbarone; meterelin; methioninase;metoclopramide; mifepristone; miltefosine; mirimostim; mitoguazone;mitolactol; mitonafide; mitoxantrone; mofarotene; molgramostim;mopidamol; maytansine; megestrol acetate; melengestrol acetate;melphalan; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitinmitomycin; mitosper; mitotane; mitoxantrone;mycophenolic acid; nafarelin; nagrestip; napavin; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; oblimersen(GENASENSE); octreotide; okicenone; onapristone; ondansetron;ormaplatin; oxisuran; oxaloplatin; osaterone; oxaliplatin; oxaunomycin;palauamine; palbociclib (IBRANCE); panitumumab (VECTIBIX); panomifene;pegaspargase; picibanil; pirarubicin; piritrexim; prednisone;prednisolone, paclitaxel; nab-paclitaxel (ABRAXANE); prednimustine;procarbazine; puromycin; raltitrexed; ramosetron; rapamycin (RAPAMUNE);rhizoxin; ribociclib (KISQALI), rituximab; rogletimide; rohitukine;romurtide; roquinimex; romidepsin; safingol; saintopin; sargramostim;semustine; sizofiran; sobuzoxane; sorafenib (NEXAVAR); sunitinib;spiromustine; squalamine; suradista; suramin; s wains onine;spiroplatin; streptonigrin; streptozocin; sulofenur; tallimustine;tamoxifen; tauromustine; tazarotene; tellurapyrylium; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thrombopoietin; thymalfasin; thymotrinan; tirapazamine; toremifene;tretinoin; trimetrexate; triptorelin; tropisetron; talisomycin;taxotere; teroxirone; testolactone; thiamiprine; thiotepa; tirapazamine;toremifene; trastuzumab; trastuzumab emtansine; trestolone acetate;triciribine phosphate; trimetrexate; uracil mustard; vandetanib(CAPRELSA); variolin B; velaresol; veramine; verteporfin; vemurafenib;vinorelbine; vinxaltine; vitaxin; vinblastine; vincristine; vindesine;vinepidine; vinglycinate; vinleurosine; vinorelbine; vinrosidine;vinzolidine; vorozole; wortmannin; zanoterone; zeniplatin; zilascorb;zinostatin stimalamer; zinostatin; and zorubicin.

In some embodiments, an anti-cancer agent includes, for example,idelalisib (ZYDELIG), docetaxel, fluorouracil, gemcitabine (GEMZAR),cisplatin, cis-diamine, carboplatin, paclitaxel, nab-paclitaxel,trastuzumab (HERCEPTIN), temozolomide, tamoxifen, 4-hydroxytamoxifen,and doxorubicin.

Also included in the definition of anti-cancer agent are: (i)anti-estrogens and selective estrogen receptor modulators (SERMs),including, for example, tamoxifen, raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, andtoremifine citrate; (ii) selective estrogen receptor modulators (SERDs)such as brilanestrant, GDC-0927, GDC-9545, AZ94%, AZ9833, GNE-274, andfulvestrant (FASLODEX); (iii) aromatase inhibitors such as, for example,4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane,formestanie, fadrozole, vorozole, letrozole, and anastrozole; (iv)anti-androgens such as apalutamide, abiraterone, enzalutamide,flutamide, nilutamide, bicalutamide, leuprolide, and goserelin.

Further included in the definition of anti-cancer agents are: (iv) MEKinhibitors such as cobimetinib; (v) lipid kinase inhibitors, such astaselisib; (vi) antisense oligonucleotides such as oblimersen; (vii)ribozymes such as VEGF expression inhibitors such as angiozyme; (viii)vaccines such as gene therapy vaccines, for example, ALLOVECTTN,LEUVECTTN, and VAXID; (ix) topoisomerase 1 inhibitors such asLURTOTECAN®; ABARELIX® rmRH; and (x) anti-angiogenic agents such asbevacizumab.

In some embodiments herein, the anti-cancer agents is a therapeuticantibody such as atezolizumab, nivolumab, daratumumab, pembrolizumab,alemtuzumab, bevacizumab; cetuximab; panitumumab, rituximab, pertuzumab,trastuzumab, trastuzumab emtansine, or tositumomab.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound can beidentified using routine techniques and their activities determinedusing tests such as those described herein. Such products can result forexample from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, provided herein aremetabolites of compounds or pharmaceutically acceptable salts thereofdescribed herein, including compounds produced by a process comprisingcontacting a Formula I compound or a pharmaceutically acceptable saltthereof with a mammal for a period of time sufficient to yield ametabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds or pharmaceutically acceptable salts thereofdescribed herein can contain asymmetric or chiral centers, and thereforeexist in different stereoisomeric forms. It is intended that allstereoisomeric forms of the compounds or pharmaceutically acceptablesalts thereof described herein, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixtures thereofsuch as racemic mixtures, form part of this disclosure. Many organiccompounds exist in optically active forms, i.e., they have the abilityto rotate the plane of plane-polarized light. In describing an opticallyactive compound, the prefixes D and L, or R and S, are used to denotethe absolute configuration of the molecule about its chiral center(s).The prefixes d and l or (+) and (−) are employed to designate the signof rotation of plane-polarized light by the compound, with (−) or lmeaning that the compound is levorotatory. A compound prefixed with (+)or d is dextrorotatory. For a given chemical structure, thesestereoisomers are identical except that they are mirror images of oneanother. A specific stereoisomer can also be referred to as anenantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which can occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity. Enantiomers canbe separated from a racemic mixture by a chiral separation method, suchas supercritical fluid chromatography (SFC). Assignment of configurationat chiral centers in separated stereoisomers can be tentative, anddepicted in Table 1 structures for illustrative purposes, beforestereochemistry is definitively established, such as from x-raycrystallographic data.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, and/or the mammal being treated therewith.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, aryl-aliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid “mesylate”, ethanesulfonic acid, p-toluenesulfonic acid, andsalicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and polyamine resins.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound described herein. Examples of solvents thatform solvates include, but are not limited to, water (i.e., “hydrate”),isopropanol, ethanol, methanol, DMSO, ethylacetate (EtOAc), acetic acid(AcOH), and ethanolamine.

The term “EC₅₀” is the half maximal effective concentration” and denotesthe plasma concentration of a particular compound required for obtaining50% of the maximum of a particular effect in vivo.

The term “Ki” is the inhibition constant and denotes the absolutebinding affinity of a particular inhibitor to a receptor. It is measuredusing competition binding assays and is equal to the concentration wherethe particular inhibitor would occupy 50% of the receptors if nocompeting ligand (e.g. a radioligand) was present. Ki values can beconverted logarithmically to pKi values (-log Ki), in which highervalues indicate exponentially greater potency.

The term “IC₅₀” is the half maximal inhibitory concentration and denotesthe concentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (-log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed, and can be converted to an absolute inhibitionconstant (Ki) using the Cheng-Prusoff equation (Biochem Pharmacol.(1973) 22:3099). Other percent inhibition parameters, such as IC₇₀,IC₉₀, etc., can be calculated.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds orpharmaceutically acceptable salts thereof described herein describedherein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl, and ¹²⁵I. Various isotopically labeled compounds orpharmaceutically acceptable salts thereof described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated. Such isotopically labeled compounds can be useful inmetabolic studies, reaction kinetic studies, detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Deuteriumlabeled or substituted therapeutic compounds or pharmaceuticallyacceptable salts thereof described herein can have improved DMPK (drugmetabolism and pharmacokinetics) properties, relating to distribution,metabolism, and excretion (ADME). Substitution with heavier isotopessuch as deuterium can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements. An 18F labeled compound can beuseful for PET or SPECT studies. Isotopically labeled compounds orpharmaceutically acceptable salts thereof described herein thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., ²H or D) can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the formula(I). The concentration of such a heavier isotope, specificallydeuterium, can be defined by an isotopic enrichment factor. In thecompounds or pharmaceutically acceptable salts thereof described hereindescribed herein, any atom not specifically designated as a particularisotope is meant to represent any stable isotope of that atom. Unlessotherwise stated, when a position is designated specifically as “H” or“hydrogen”, the position is understood to have hydrogen at its naturalabundance isotopic composition. Accordingly, in the compounds orpharmaceutically acceptable salts thereof described herein any atomspecifically designated as a deuterium (D) is meant to representdeuterium.

Phenoxy-Pyridyl-Pyrimidine Compounds

The compounds disclosed herein are compounds of Formula (I) orpharmaceutically acceptable salts, solvates (e.g., hydrates), prodrugs,metabolites, or derivatives thereof, and pharmaceutical compositionsthereof, which are potentially useful in the treatment of diseases,conditions and/or disorders modulated by inositol requiring enzyme 1(IRE1). In one aspect provided herein are compounds of Formula (I) orpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising such compounds.

In one aspect, provided is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R⁰ is hydrogen or fluoro;

R¹ is C₃₋₁₂ cycloalkyl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —(C₁₋₆ alkylene)-(C₃-C₁₂ cycloalkyl), or —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), —(C₁₋₆ alkylene)-OR^(1c), or—(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C₁₋₆alkylene of R¹ are independently optionally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰;

each R^(1a), R^(1b) and R^(1c) is independently hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(1a) and R^(1b) are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

R^(2A) and R^(2B) are independently hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆haloalkyl);

R³ is hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆ haloalkyl);

R⁴ and R⁵ are independently hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR^(7A),—NR^(8A)R^(8B), —NR⁸C(O)R⁷, —NR⁸C(O)OR^(7A), —NR⁸C(O)NR^(8A)R^(8B),—NR⁸SO₂R⁹, —NR⁸SO₂NR^(8A)R^(8B), —NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹,—C(O)NR^(8A)R^(8B), —C(O)R⁷, —C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹,or —SO₂NR^(8A)R^(8B); wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroarylof R⁴ and R⁵ are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

n is 0, 1, 2, or 3;

each R⁶ is independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), —O(C₁₋₆ haloalkyl), —SO₂C₁₋₆alkyl) or —SO₂(C₁₋₆ haloalkyl);

each R⁷ is independently hydrogen, NHR⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, 5- to 14-membered heteroaryl, or 3- to 12-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, 5-to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R⁷ andR^(7A) are optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰;

each R^(7A) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to12-membered heterocyclyl of R⁷ and R^(7A) are optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰;

each R⁸ is independently hydrogen or C₁-C₆ alkyl;

each R^(8A) is independently hydrogen or C₁-C₆ alkyl;

each R^(8B) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₅ cycloalkyl, C₆₋₁₀ aryl, and 3- to12-membered heterocyclyl of R^(8B) are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰;

each R^(8C) is independently hydrogen or C₁-C₆ alkyl;

each R⁹ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

each R¹⁰ is independently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to12-membered heterocyclyl, halogen, cyano, —C(O)R^(a), —C(O)OR^(b),—C(O)NR^(c)R^(d), —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —SR^(b),—S(O)R^(e), —S(O)₂R^(e), —S(O)(═NH)R^(e), —S(O)₂NR^(c)R^(d),—NR^(c)R^(d), —N(R^(f))C(O)R^(a), —N(R^(f))C(O)OR^(b),—N(R^(f))C(O)NR^(c)R^(d), —N(R^(f))S(O)₂R^(e), —N(R^(f)S(O)₂NR^(c)R^(d),—P(O)R^(g)R^(h), or —SiR^(i)R^(j)R^(k); wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-memberedheteroaryl and 3- to 14-membered heterocyclyl of R¹⁰ are each optimallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹;

each R^(a) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 12-membered heterocyclyl of R^(a) are each optimally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹¹;

each R^(b) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl and 3- to 12-membered heterocyclyl of R^(b) are eachoptimally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹;

each R^(c) and R^(d) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(c) and R^(d) are each optimally substituted with 1, 2, 3 or 4substituents independently selected fromR¹¹;

-   -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a 4- to 12-membered heterocyclyl        optimally substituted with 1, 2, 3 or 4 substituents        independently selected from R¹¹;

each R^(e) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 12-membered heterocyclyl of R^(e) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹;

each R^(f) is independently hydrogen or C₁₋₆ alkyl;

each R^(g) and R^(h) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or—O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R^(g)and R^(h) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹;

-   -   or R^(g) and R^(h) are taken together with the phosphorus atom        to which they are attached to form a 4- to 12-membered        heterocyclyl optimally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹;

each R^(i), R^(j) and R^(k) is independently C₁₋₆ alkyl;

each R¹¹ is independently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to8-membered heterocyclyl, halogen, cyano, —C(O)R^(a1), —C(O)OR^(b1),—C(O)NR^(c1)R^(d1), —OR^(b1), —OC(O)R^(a1), —OC(O)NR^(c1)R^(d1),—SR^(b1), —S(O)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(c1)R^(d1),—NR^(c1)R^(d1), —N(R^(f1))C(O)R^(a1), —N(R^(f1))C(O)OR^(b1),—N(R^(f1))C(O)NR^(c1)R^(d1), —N(R^(f1))S(O)₂R^(e1),—N(R^(f1))S(O)₂NR^(c1)R^(d1), —P(O)R^(g1)R^(h1), or—SiR^(i1)R^(j1)R^(k1); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and3- to 14-membered heterocyclyl of R¹¹ are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²;

each R^(a1) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 8-membered heterocyclyl of R^(a1) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²;

each R^(b1) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to 8-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(b1) areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹²;

each R^(c1) and R^(d1) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to 8-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(c1) andR^(d1) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹²;

-   -   or R^(c1) and R^(d1) are taken together with the nitrogen atom        to which they are attached to form a 4- to 8-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹²;

each R^(e1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 8-membered heterocyclyl of R^(e1) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹²;

each R^(f1) is independently hydrogen or C₁₋₆ alkyl;

each R^(g1) and R^(h1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl,or —O—C₁₋₆ alkyl; herein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(g1)and R^(h1) are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²;

-   -   or R^(g1) and R^(h1) are taken together with the phosphorus atom        to which they are attached to form a 4- to 8-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹²;

each R^(i1), R^(j1) and R^(k1) is independently C₁₋₆ alkyl;

each R¹² is independently oxo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5-to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano,—C(O)R^(a2), —C(O)OR^(b2), —C(O)NR^(c2)R^(d2), —OR^(b2), —OC(O)R^(a2),—OC(O)NR^(c2)R^(d2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(d2), —NR^(c2)R^(d2),—N(R^(f2))C(O)R^(a2), —N(R^(n))C(O)OR^(b2), —N(R^(f2))C(O)NR^(c2)R^(d2),—N(R^(f2))S(O)₂R^(e2), —N(R^(f2))S(O)₂NR^(c2)R^(d2), or—P(O)R^(g2)R^(h2); wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5-to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R¹² areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R^(a2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-memberedheteroaryl and 3- to 6-membered heterocyclyl of R^(a2) are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R^(b2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or 3-to 6-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl and3- to 6-membered heterocyclyl of R^(b2) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹³;

each R^(c2) and R^(d2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or 3- to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl,C₃₋₆ cycloalkyl and 3- to 8-membered heterocyclyl of R^(c2) and R^(d2)are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³;

-   -   or R^(c2) and R^(d2) are taken together with the nitrogen atom        to which they are attached to form a 4- to 6-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹³;

each R^(e2) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to6-membered heteroaryl or 3- to 6-membered heterocyclyl; wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl and 3- to6-membered heterocyclyl of are each optimally substituted with 1, 2, 3or 4 substituents independently selected from R¹³;

each R^(f2) is independently hydrogen or C₁₋₆ alkyl;

each R^(g2) and R^(h2) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-to 8-membered heterocyclyl, or —O—C₁₋₆ alkyl; herein the C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and 3- to 8-membered heterocyclyl of R^(g2) and R^(h2)are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³;

-   -   or R^(g2) and R^(h2) are taken together with the phosphorus atom        to which they are attached to form a 4- to 6-membered        heterocyclyl optimally substituted with 1, 2, 3 or 4        substituents independently selected from R¹³; and

each R¹³ is independently oxo, halogen, hydroxyl, —O(C₁₋₆ alkyl), cyano,C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments of the compound of the Formula I, or stereoisomers,tautomers, or pharmaceutically acceptable salts thereof, the compound isother than Compound Nos. 1x-12x of Table 1X. In some embodiments of theFormula I, or stereoisomers, tautomers, or pharmaceutically acceptablesalts thereof, wherein R^(8B) is other than hydrogen or optimallysubstituted phenyl. In some embodiments of the Formula I, orstereoisomers, tautomers, or pharmaceutically acceptable salts thereof,wherein R⁴ is other than —NHC(O)NH—R^(8B) wherein R^(8B) is optimallysubstituted phenyl or optionally substituted alkyl.

TABLE 1X No. Name  1x Benzamide,3-[[3-[2-[[2-(diethylamino)ethyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]-4-methyl-N-[2-methyl-3-(1-methylethyl)phenyl]-  2x2-Pyrrolidinone, 1-[3-[[4-[2-(4-amino-2-methylphenoxy)-3-pyridinyl]-2-pyrimidinyl]amino]propyl]-  3x 4-Morpholinepropanamine,N-[4-[2-(4-amino-2-methylphenoxy)-3-pyridinyl]-2- pyrimidinyl]-  4xUrea,N-(3-fluoro-4-methylphenyl)-N′-[4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-  5x Urea,N-(2,3-dihydro-1H-inden-5-yl)-N′-[4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-  6xUrea,N-(4-chlorophenyl)-N′-[4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-  7x Urea,N-[3-methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-N′-[3-(trifluoromethyl)phenyl]-  8xUrea, N-(5-chloro-2-methoxyphenyl)-N′-[3-methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-  9xUrea, N-(5-chloro-2-methoxyphenyl)-N′-[3-methyl-4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]- 10xBenzamide, 3-[[3-[2-[[2-(diethylamino)ethyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]-4-methyl-N-[2-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-11x Benzamide, N-(5-cyclohexyl-2-methoxyphenyl)-3-[[3-[2-[[2-(diethylamino)ethyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]-4-methyl- 12xBenzamide, 3-[[3-[2-[[2-(diethylamino)ethyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]-4-methyl-N-[3-(1-methylethyl)phenyl]-

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein R⁰ is hydrogen orfluoro. In some embodiments, R⁰ is H.

In some embodiments, the compound is of the Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(2A) and R^(2B) areindependently hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆ haloalkyl). In some embodiments,R^(2A) and R^(2B) are independently hydrogen, halogen, cyano, C₁₋₆alkyl, or —O(C₁₋₆alkyl). In some embodiments, R^(2A) and R^(2B) areindependently H, F, Cl or C₁-C₆ alkyl (e.g., methyl). In someembodiments, one of R^(2A) and R^(2B) is hydrogen and the other one ofR^(2A) and R^(2B) is hydrogen, fluoro or methyl. In some embodiments,R^(2A) and R^(2B) are each hydrogen. In some embodiments, R^(2A) andR^(2B) are each fluoro. In some embodiments, R^(2A) and R^(2B) are eachmethyl. In some embodiments, R^(2A) is H, F or methyl, and R^(2B) is H,F, Cl or —CH₃.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein R³ is hydrogen,halogen, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆alkyl), or —O(C₁₋₆ haloalkyl). In some embodiments, R³ is hydrogen,halogen, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or —O(C₁₋₆ alkyl). In someembodiments, R³ is H, F, Cl, —CN, C₁₋₆ alkyl (e.g., methyl), or C₁₋₆haloalkyl (e.g., trifluoromethyl). In one variation, R³ is H, F, Cl,—CN, —CH₃, or —CF₃.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein 0, 1, 2, or 3; andeach R⁶ is independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), —O(C₁₋₆ haloalkyl),—SO₂(C₁₋₆ alkyl) or —SO₂(C₁₋₆ haloalkyl). In some embodiments, n is 0.(i.e., R⁶ is absent). In some embodiments, n is 1 and R⁶ is F, Cl, —CN,—NO₂, —O—(C₁₋₆ alkyl) or C₁₋₆ alkyl. In some embodiments, n is 1 and R⁶is F, Cl, —CN, —O—(C₁₋₆ alkyl) (e.g., —OCH₃), or C₁₋₆ alkyl (e.g.,methyl and ethyl).

It is intended and understood that each and every variation of R⁰,R^(2A), R^(2B), R³, R⁶ and n described for the Formula (I) can becombined, the same as if each and every combination is specifically andindividully described. For example, in some embodiments, R⁰ is H; R^(2A)and R^(2B) are independently H, F, Cl or C₁-C₆ alkyl (e.g., methyl); R³is H, F, Cl, —CN, C₁₋₆ alkyl (e.g., methyl), or C₁₋₆ haloalkyl (e.g.,trifluoromethyl); n is 0 and R⁶ is absent. In one variation, R⁰ is H;R^(2A) and R^(2B) are independently H, F, Cl or methyl; R³ is H, F, Cl,—CN, methyl, or trifluoromethyl; and n is 0.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen,halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₂₀ aryl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —OR^(7A), —NR^(8A)R^(8B), —NR⁸C(O)R⁷,—NR⁸C(O)OR^(7A), —NR⁸C(O)NR^(8A)R^(8B), —NR⁸SO₂R⁹, —NR⁸SO₂NR^(8A)R^(8B),—NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹, —C(O)NR^(8A)R^(8B), —C(O)R⁷,—C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹, or —SO₂NR^(8A)R^(8B);wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl, 3- to 14-memberedheterocyclyl, and 5- to 14-membered heteroaryl of R⁵ are optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰. In some embodiments, R⁵ is H, F, Cl, —CN, or C₁₋₆ alkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰. In some embodiments, R⁵ is H, F, Cl, —CN, C₁₋₆ alkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹. Insome embodiments, R⁵ is H, F, Cl, —CN, C₁₋₆ alkyl (e.g., —CH₃) or C₁₋₆haloalkyl (e.g., —CF₃). In some embodiments, R⁵ is H, F, Cl, —CN, —CH₃,or —CF₃. In one embodiment, R⁵ is NHC(O)NHR⁹, where R⁹ is as describedherein.

In some embodiments, R⁵ is C₁₋₆ alkyl substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B),or —C(O)N(R⁸)SO₂R⁹. In some of these embodiments, R⁴ is H, F, Cl, —CN,C₁₋₆ alkyl (e.g., —CH₃) or C₁₋₆ haloalkyl (e.g., —CF₃). In some of theseembodiments, R⁴ is H, F, Cl, —CN, —CH₃, or —CF₃. In one variation, R⁴ isH, and R⁵ is —(C₁₋₆ alkylene)-N(R^(f))C(O)R^(a); C₁₋₆ alkyl substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰,—NH—SO₂R⁹, —NH—R^(8B), or —C(O)NH—SO₂R⁹. In a specific variation, R⁵ is—CH₂NHC(O)-(cyclopropyl), —NHCH₂CH(OH)CF₃ or—C(O)NHSO₂-(2-chlorophenyl). In another variation, R⁵ is —NHSO₂R⁹, andR⁹ is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, or C₆₋₁₀ aryl optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰. In another specific variation, R⁵ is —NHSO₂-(2-chlorophenyl),—NHSO₂—CH₂CH₂CH₃ or —NHSO₂—CH₂-(phenyl).

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen,halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₂₀ aryl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —OR^(7A), —NR^(8A)R^(8B), —NR⁸C(O)R⁷,—NR⁸C(O)OR^(7A), —NR⁸C(O)NR^(8A)R^(8B), —NR⁸SO₂R⁹, —NR⁸SO₂NR^(8A)R^(8B),—NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹, —C(O)NR^(8A)R^(8B), —C(O)R⁷,—C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹, or —SO₂NR^(8A)R^(8B);wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl, 3- to 14-memberedheterocyclyl, and 5- to 14-membered heteroaryl of R⁴ and R⁵ areoptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰. In some embodiments, R⁴ is hydrogen, halogen, cyano,nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀aryl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl,—OR^(7A), —NR^(8A)R^(8B), —NR⁸C(O)R⁷, —NR⁸C(O)OR^(7A), —NR⁸SO₂R⁹,—NR⁸SO₂NR^(8A)R^(8B), —NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹,—C(O)NR^(8A)R^(8B), —C(O)R⁷, —C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹,or —SO₂NR^(8A)R^(8B); wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroarylof R⁴ and R⁵ are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰; wherein R⁸ and R^(8A) areindependently hydrogen or C₁-C₆ alkyl, and R^(8B) is independently C₁₋₆alkyl, C₁₋₆ alkenyl, C₃₋₈ cycloalkyl, or 3- to 12-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, and 3- to12-membered heterocyclyl of R^(8B) are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰. In someembodiments, R⁴ is —NR⁸C(O)R⁷ or —NR⁸SO₂R⁹. In some of theseembodiments, R⁵ is H, F, Cl, —CN, —CH₃, or —CF₃.

In some embodiments, R⁴ is —NHC(O)R⁷, wherein R⁷ is C₁₋₆ alkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰, or C₃₋₈ cycloalkyl optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰. In someparticular embodiments, R⁷ is cyclopropyl, spiro[2.2]pentyl,cyclohexylmethyl or 4-chlorobenzyl. In some embodiments, R⁷ iscyclopentyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-cyanophenyl,4-cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,4-(trifluoromethoxy)phenyl, 3,5-difluorophenyl, 3-pyridyl,1-methyl-1H-imidazol-4-yl, 1-methyl-1H-pyrazol-4-yl, benzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-cyanobenzyl,4-cyanobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,(1-methyl-1H-pyrazol-3-yl)methyl, (5-methylisoxazol-3-yl)methyl,(pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl,cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl,(3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl,(spiro[3.3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, n-propyl, 3-cyano-2,2-dimethylpropyl,3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl,3,3-dimethylbutyl, 3-cyano-3-methylbutyl, or 4,4-dimethylpentyl.

In some embodiments, R⁴ is —NH—SO₂R⁹, wherein R⁹ is C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, or 5- to 14-membered heteroaryl, wherein theC₁₋₆ alkyl, Cis cycloalkyl, C₆₋₁₀ aryl and 5- to 14-membered heteroarylof R⁹ are independently optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰. In some of theseembodiments, R⁹ is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or5 substituents independently selected from R¹⁰. In some of theseembodiments, R⁹ is C₁₋₆ haloalkyl (e.g., C₁₋₆ fluoroalkyl). In some ofthese embodiments, R⁹ is C₃₋₈ cycloalkyl optimally substituted with 1,2, 3, 4 or 5 substituents independently selected from R¹⁰. In some ofthese embodiments, R⁹ is C₆₋₁₀ aryl optimally substituted with 1, 2, 3,4 or 5 substituents independently selected from R¹⁰. In some of theseembodiments, R⁹ is phenyl substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰. In some of these embodiments, R⁹ is 5-to 14-membered heteroaryl optimally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰.

In some embodiments, R⁹ is C₁₋₆ haloalkyl (e.g., C₁₋₆ fluoroalkyl). Insome embodiments, R⁹ is benzyl optimally substituted with 1, 2, 3, 4 or5 substituents independently selected from R¹⁰. In some embodiments, R⁹is benzyl where the phenyl ring is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁰. In some embodiments, R⁹ isbenzyl optimally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from the group consisting of fluoro, chloro,bromo, —CH₃, —CH₂CH₃, —CH₂OH, and —CN.

In some particular embodiments, R⁹ is cyclopentyl, cyclohexyl, phenyl,2-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-(difluoromethoxy)phenyl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,3,5-difluorophenyl, 3-pyridyl, 1-methyl-1H-imidazol-4-yl,1-methyl-1H-pyrazol-4-yl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 3-chlorobenzyl,4-chlorobenzyl, (1-methyl-1H-pyrazol-3-yl)methyl,(5-methylisoxazol-3-yl)methyl, (pyridin-2-yl)methyl,(pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl,cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl,(3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl,(spiro[3.3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, n-propyl, 3-cyano-2,2-dimethylpropyl,3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl,3,3-dimethylbutyl, 3-cyano-3-methylbutyl, or 4,4-dimethylpentyl. In someparticular embodiments, R⁹ is cyclopropyl, spiro[2.2]pentyl,cyclohexylmethyl or 4-chlorobenzyl. In some embodiments, R⁹ is selectedfrom the group consisting of benzyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, cyclopentanyl, cyclopentanylmethyl,cyclohexyl, cyclohexylmethyl, pyrrolidin-1-yl, piperidin-1-yl, pyridyl,pyridylmethyl, tetrahydrofuranyl, tetrahydrofuranylmethyl, andtetrahydropyranyl, tetrahydropyranylmethyl, thiazolyl, andthiazolylmethyl; each of which is optionally and independentlysubstituted with one or more substituents selected from fluoro, chloro,bromo, —CH₃, —CH₂CH₃, —CH₂OH, and —CN.

In some embodiments, R⁴ is —NHC(O)R⁷, wherein R⁷ is cyclopropyl,spiro[2.2]pentyl, cyclohexylmethyl or 4-chlorobenzyl. In one embodiment,R⁴ is NHC(O)NHR⁹, where R⁹ is as described herein.

In some embodiments, R⁴ is —NH—SO₂R⁹, wherein R⁹ is cyclopentyl,cyclohexyl, phenyl, 2-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,4-(trifluoromethoxy)phenyl, 3,5-difluorophenyl, 3-pyridyl,1-methyl-1H-imidazol-4-yl, 1-methyl-1H-pyrazol-4-yl, benzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-cyanobenzyl,4-cyanobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,(1-methyl-1H-pyrazol-3-yl)methyl, (5-methylisoxazol-3-yl)methyl,(pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl,cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl,(3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl,(spiro[3.3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, n-propyl, 3-cyano-2,2-dimethylpropyl,3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl,3,3-dimethylbutyl, 3-cyano-3-methylbutyl, or 4,4-dimethylpentyl.

In some embodiments, R⁵ is cyclopropanecarboxamidomethyl,(3,3,3-trifluoro-2-hydoxy-1-propyl)amino, or2-chlorobenzenesulfonamidocarbonyl. In some embodiments, R⁵ is—NH—SO₂R⁹, wherein R⁹ is 2-chloropheyl, benzyl or n-propyl. In some ofthese embodiments, R⁴ is H.

It is intended and understood that each and every variation of R⁰,R^(2A), R^(2B), R³, R⁶ and n, or a combination thereof, described forthe Formula (I) can be combined with each and every variation of R⁴ andR⁵, or combinations thereof, described for the Formula (I), the same asif each and every combination is specifically and individully described.For example, in some embodiments, R⁰ is H; R^(2A) and R^(2B) areindependently H, F, Cl or C₁-C₆ alkyl (e.g., methyl); R³ is H, F, Cl,—CN, C₁₋₆ alkyl (e.g., methyl), or C₁₋₆ haloalkyl (e.g.,trifluoromethyl); n is 0; R⁴ is —NR⁸C(O)R⁷ or —NR⁸SO₂R⁹; and R⁵ is H, F,Cl, —CN, C₁₋₆ alkyl (e.g., —CH₃) or C₁₋6 haloalkyl (e.g., —CF₃). In onevariation, R⁰ is H; R^(2A) and R^(2B) are independently H, F, Cl ormethyl; R³ is H, F, Cl, —CN, methyl, or trifluoromethyl; n is 0; R⁴ is—NR⁸C(O)R⁷ or —NR⁸SO₂R⁹; R⁵ is H, F, Cl, —CN, —CH₃, or —CF₃; R⁷ is C₁₋₆alkyl optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰, or C₃₋₈ cycloalkyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰; and R⁹ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, or 5- to14-membered heteroaryl, herein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl and 5- to 14-membered heteroaryl of R⁹ are independently optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰. In some embodiments, R⁰ is H; R^(2A) and R^(2B) areindependently H, F, Cl or C₁-C₆ alkyl (e.g., methyl); R³ is H, F, Cl,—CN, C₁₋₆ alkyl (e.g., methyl), or C₁₋₆ haloalkyl (e.g.,trifluoromethyl); n is 0; R⁴ is H, F, Cl, —CN, C₁₋₆ alkyl (e.g., —CH₃)or C₁₋₆ haloalkyl (e.g., —CF₃); and R⁵ is C₁₋₆ alkyl substituted with 1,2, 3, 4 or 5 substituents independently selected from R¹⁰, —NR⁸SO₂R⁹,—NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹. In one variation, R⁰ is H; R^(2A)and R^(2B) are independently H, F, Cl or methyl; R³ is H, F, Cl, —CN,methyl, or trifluoromethyl; n is 0; R⁴ is H, and R⁵ is —(C₁₋₆alkylene)-N(R^(f))C(O)R^(a); C₁₋₆ alkyl substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, —NH—SO₂R⁹, —NH—R^(8B), or—C(O)NH—SO₂R⁹.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein R¹ is C₃₋₁₂cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-memberedheteroaryl, —(C₁₋₆ alkylene)-(C₃-C₁₂ cycloalkyl), or —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), —(C₁₋₆ alkylene)-OR^(1c), or—(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C₁₋₆alkylene of R¹ are independently optimally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰. In some embodiments,R¹ is C₃₋₁₂ cycloalkyl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —(C₁₋₆ alkylene)-(C₃-C₁₂ cycloalkyl), or —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), or —(C₁₋₆alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to 14-memberedheterocyclyl, 5- to 14-membered heteroaryl, and C₁₋₆ alkylene of R¹ areindependently optimally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰. In some embodiments, R¹ is C₃₋₁₂cycloalkyl; 3- to 14-membered heterocyclyl; —(C₁₋₆ alkylene)-(3- to14-membered heterocyclyl), or —(C₁₋₆ alkylene)-NR^(1a)R^(1b); whereinthe C₃₋₁₂ cycloalkyl, 3- to 14-membered heterocyclyl, and C₁₋₆ alkyleneof R¹ are independently optimally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰. In some embodiments, R¹ isC₃₋₁₂ cycloalkyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰. In some embodiments, R¹ is3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or5 substituents independently selected from R¹⁰. In some embodiments, R¹is cyclohexyl or piperidinyl, each is independently optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom the group consisting of F, —CH₃, —OH, oxo, and —NH₂. In some ofthese embodiments, R¹ is selected from the group consisting ofpiperidin-3-yl, 5-fluoropiperidin-3-yl, 5-methylpiperidin-3-yl and5-fluoro-5-methylpiperidin-3-yl. In some of these embodiments, R¹ is—(C₁₋₆ alkylene)-(3- to 14-membered heterocyclyl) optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰. Insome embodiments, R¹ is —(C₁₋₆ alkylene)-NR^(1a)R^(1b). In some of theseembodiments, R^(1a) and R^(1b) are independently hydrogen or C₁₋₆ alkyl.

It is intended and understood that each and every variation of R⁰,R^(2A), R^(2B), R³, R⁴, R⁵, R⁶ and n, or a combination thereof,described for the Formula (I) can be combined with each and everyvariation of R¹ described for the Formula (I), the same as if each andevery combination is specifically and individually described. Forexample, in some embodiments, R⁰ is H; R¹ is C₃₋₁₂ cycloalkyl; 3- to14-membered heterocyclyl; —(C₁₋₆ alkylene)-(3- to 14-memberedheterocyclyl), or —(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂cycloalkyl, 3- to 14-membered heterocyclyl, and C₁₋₆ alkylene of R¹ areindependently optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰; R^(2A) and R^(2B) are independently H,F, Cl or C₁-C₆ alkyl (e.g., methyl); R³ is H, F, Cl, —CN, C₁₋₆ alkyl(e.g., methyl), or C₁₋₆ haloalkyl (e.g., trifluoromethyl); n is 0; R⁴ is—NR⁸C(O)R⁷ or —NR⁸SO₂R⁹; and R⁵ is H, F, Cl, —CN, C₁₋₆ alkyl (e.g.,—CH₃) or C₁₋₆ haloalkyl (e.g., —CF₃). In one variation, R⁰ is H; R¹ ispiperidin-3-yl, 5-fluoropiperidin-3-yl, 5-methylpiperidin-3-yl or5-fluoro-5-methylpiperidin-3-yl; R^(2A) and R^(2B) are independently H,F, Cl or methyl; R³ is H, F, Cl, —CN, methyl, or trifluoromethyl; n is0; R⁴ is —NR⁸C(O)R⁷ or —NR⁸SO₂R⁹; R⁵ is H, F, Cl, —CN, —CH₃, or —CF₃; R⁷is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰, or C₃₋₈ cycloalkyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰; and R⁹ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, or 5- to14-membered heteroaryl, wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl and 5- to 14-membered heteroaryl of R⁹ are independently optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰.

In some embodiments, R⁰ is H; R¹ is C₃₋₁₂ cycloalkyl; 3- to 14-memberedheterocyclyl; —(C₁₋₆ alkylene)-(3- to 14-membered heterocyclyl), or—(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to14-membered heterocyclyl, and C₁₋₆ alkylene of R¹ are independentlyoptimally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰; R^(2A) and R^(2B) are independently H, F, Cl or C₁-C₆alkyl (e.g., methyl); R³ is H, F, Cl, —CN, C₁₋₆ alkyl (e.g., methyl), orC₁₋₆ haloalkyl (e.g., trifluoromethyl); n is 0; R⁴ is H, F, Cl, —CN,C₁₋₆ alkyl (e.g., —CH₃) or C₁₋₆ haloalkyl (e.g., —CF₃); and R⁵ is C₁₋₆alkyl substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹. In onevariation, R⁰ is H; R¹ is piperidin-3-yl, 5-fluoropiperidin-3-yl,5-methylpiperidin-3-yl or 5-fluoro-5-methylpiperidin-3-yl; R^(2A) andR^(2B) are independently H, F, Cl or methyl; R³ is H, F, Cl, —CN,methyl, or trifluoromethyl; n is 0; R⁴ is H, and R⁵ is —(C₁₋₆alkylene)-N(R^(f))C(O)R^(a); C₁₋₆ alkyl substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, —NH—SO₂R⁹, —NH—R^(8B), or—C(O)NH—SO₂R⁹.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein the compound is of theFormula (Ia):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁵, R⁶ andR⁹ are as detailed herein for Formula (I) or variations thereof. In someembodiments, each R^(6A) and R^(2A) is H, each R²⁸, R³ and R⁵ is F, andR¹ and R⁹ are as detailed herein for Formula (I).

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein the compound is of theFormula (Ib):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁵, R⁶ andR⁷ are as detailed herein for Formula (I) or variations thereof. In someembodiments, each R^(6A) and R^(2A) is H, each R^(2B), R³ and R⁵ is F,and R¹ and R⁷ are as detailed herein for Formula (I). In one embodiment,R⁷ is NHR⁹, where R⁹ is as described herein.

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein the compound is of theFormula (Ic):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁶ and R⁹are as detailed herein for Formula (I).

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein the compound is of theFormula (Id):

herein R^(6A) is hydrogen or R⁶; R²¹ and R²² are independently H, F,—CH₃ or —NH₂; and R^(2A), R^(2B), R³, R⁴, R⁵ and R⁶ are as detailedherein for Formula (I) or variations thereof. In some embodiments, eachR^(6A) and R^(2A) is H, each R^(2B), R³ and R⁵ is F, and R⁴ is asdetailed herein for Formula (I).

In some embodiments, the compound is of the Formula (Id-1), (Id-2),(Id-3), (Id-4), (Id-5), (Id-6) or (Id-7):

or a pharmaceutically acceptable salt thereof, wherein R^(6A) ishydrogen or R⁶; and R^(2A), R^(2B), R³, R⁴, R⁵ and R⁶ are as detailedherein for Formula (I) or variations thereof. In some embodiments, eachR^(6A) and R^(2A) is H, each R^(2B), R³ and R⁵ is F, and R⁴ is asdetailed herein for Formula (I).

In some embodiments, the compound is of the Formula (I) or apharmaceutically acceptable salt thereof, wherein the compound is of theFormula (Ie):

wherein R^(6A) is hydrogen or R⁶; R²¹ and R²² are independently H, F,—CH₃ or —NH₂; and R^(2A), R^(2B), R³, R⁵, R⁶ and R⁹ are as detailedherein for Formula (I) or variations thereof. In some embodiments, eachR^(6A) and R^(2A) is H, each R^(2B), R³ and R⁵ is F, and R⁹ is asdetailed herein for Formula (I).

In some embodiments, the compound is of the Formula (Ie-1), (Ie-2),(Ie-3), (Ie-4), (Ie-5), (Ie-6) or (Ie-7):

or a pharmaceutically acceptable salt thereof, wherein R^(6A) ishydrogen or R⁶; and R^(2A), R^(2B), R³, R⁵, R⁶ and R⁹ are as detailedherein for Formula (I). In some embodiments, each R^(6A) and R^(2A) isH, each R^(2B), R³ and R⁵ is F, and R⁹ is as detailed herein for Formula(I).

In some embodiments of the compound or pharmaceutically acceptable saltthereof of the Formula (Ia), (Ib), (Ic), (Id), (Id-1), (Id-2), (Id-3),(Id-4), (Id-5), (Id-6), (Id-7), (Ie), (Ie-1), (Ie-2), (Ie-3), (Ie-4),(Ie-5), (Ie-6) or (Ie-7), or variations thereof, R^(6A) is H.

In some embodiments of the compound or pharmaceutically acceptable saltthereof of the Formula (I), or variations thereof where applicable, or asalt (e.g., a pharmaceutically acceptable salt) thereof, each R¹⁰ isindependently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to 12-memberedheterocyclyl, halogen, cyano, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(c)R^(d),—OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —SR^(b), —S(O)R^(e),—S(O)₂R^(e), —S(O)(═NH)R^(e), —S(O)₂NR^(c)R^(d), —NR^(c)R^(d),—N(R^(f))C(O)R^(a), —N(R^(f))C(O)OR^(b), —N(R^(f))C(O)NR^(c)R^(d),—N(R^(f))S(O)₂R^(e), or —N(R^(f))S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroaryl and 3- to 14-membered heterocyclyl of R¹⁰ areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹.

In one variation, R¹⁰ is independently oxo; C₁₋₆ alkyl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹; 5- to 10-membered heteroaryl optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹¹; halogen, cyano, —OR^(b),—NR^(c)R^(d), —N(R^(f))C(O)R^(a), or —N(R^(f))S(O)₂R^(e).

In one variation, R¹⁰ is independently oxo, halogen, cyano, C₁₋₆ alkyloptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹, or —OR^(b).

In one variation, R¹⁰ is independently —NR^(c)R^(d), —N(R^(f))C(O)R^(a),—N(R^(f))C(O)OR^(b), —N(R^(f))C(O)NR^(c)R^(d), —N(R^(f))S(O)₂R^(e), or—N(R^(f))S(O)₂NR^(c)R^(d).

In one variation, R¹⁰ is independently oxo, —OR^(b), —OC(O)R^(a),—OC(O)NR^(c)R^(d), —SR^(b), —S(O)R^(e), —S(O)₂R^(e), or—S(O)₂NR^(c)R^(d).

In one variation, each R¹⁰ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,3- to 12-membered heterocyclyl, halogen, cyano, —C(O)R^(a), —C(O)OR^(b),—C(O)NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and 3- to14-membered heterocyclyl of R¹⁰ are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹.

In one variation, each R¹⁰ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹.

In one variation, R¹⁰ is C₁₋₆ alkyl optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹¹. In one variation, R¹⁰is 3- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹¹.

In one variation, R¹⁰ is halogen, cyano, —NR^(c)R^(d), —C(O)NR^(c)R^(d),—OR^(b), —S(O)₂R^(e), C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OH, or —(C₁₋₆alkylene)-OH.

In one variation, R¹⁰ is hydroxyl, cyano, halogen, —CHF₂, —CF₃, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —O(C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—S(O)₂NR^(c)R^(d), —C(O)NR^(c)R^(d), or —N(R^(f))C(O)R^(a).

In some embodiments, each R^(a) is independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R^(a)are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹. In one variation, R^(a) isindependently hydrogen or C₁₋₆ alkyl. In one variation, R^(a) isindependently C₁₋₆ alkyl (e.g., methyl).

In some embodiments, each R^(b) is independently hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(b) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹. In one variation, R^(b) isindependently hydrogen or C₁₋₆ alkyl. In one variation, R^(b) isindependently C₁₋₆ haloalkyl (e.g., —CF₃).

In some embodiments, each R^(c) and R^(d) is independently hydrogen,C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or3- to 12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and 3- to 12-memberedheterocyclyl of R^(c) and R^(d) are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹; or R^(c) andR^(d) are taken together with the nitrogen atom to which they areattached to form a 4- to 12-membered heterocyclyl optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹¹. In onevariation, each R^(c) and R^(d) is independently hydrogen or C₁₋₆ alkyl.

In some embodiments, each R^(e) is independently C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(e) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹. In one variation, R^(e) isindependently C₁₋₆ alkyl. In one variation, R^(e) is phenyl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹.

In some embodiments, each R^(f) is independently hydrogen or C₁₋₆ alkyl.In one variation, R^(f) is hydrogen.

In some embodiments, each R¹¹ is independently oxo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, —C(O)R^(a1),—C(O)OR^(b1), —C(O)NR^(c1)R^(d1), —OR^(b1), —OC(O)R^(a1),—OC(O)NR^(c1)R^(d1), —SR^(b1), —S(O)R^(e1), —S(O)₂R^(e1),—S(O)₂NR^(c1)R^(d1), —NR^(c1)R^(d1), —N(R^(f1))C(O)R^(a1),—N(R^(f1))C(O)OR^(b1), —N(R^(f1))C(O)NR^(c1)R^(d1),—N(R^(f1))S(O)₂R^(e1), or —N(R^(f1))S(O)₂NR^(c1)R^(d1); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroaryl and 3- to 14-membered heterocyclyl of R¹¹ areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹².

In one variation, each R¹¹ is independently oxo, C₁₋₆ alkyl, C₃₋₆cycloalkyl, 3- to 8-membered heterocyclyl, halogen, cyano, or —OR^(b1);wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 3- to 14-memberedheterocyclyl of R¹¹ are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹².

In one variation, R¹¹ is C₁₋₆ alkyl optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹². In one variation, R¹¹is 3- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹².

In one variation, R¹¹ is halogen, cyano, —NR^(c1)R^(d1),—C(O)NR^(c1)R^(d1), —OR^(b1), —S(O)₂R^(e1), C₁₋₆ haloalkyl, —(C₁₋₆alkylene)-OH, or —(C₁₋₆ alkylene)-OH.

In one variation, R¹¹ is hydroxl, cyano, halogen, —CHF₂, —CF₃, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —O(C₁₋₆ alkyl), —SO₂(C₁₋₆ alkyl),—S(O)₂NR^(c1)R^(d1), —C(O)NR^(c1)R^(d1), or —N(R^(f1))C(O)R^(a1).

In one variation, R¹¹ is halogen, cyano, —O(C₁₋₆ alkyl), —O(C₁₋₆alkylene)-NH₂, or —(C₁₋₆alkylene)-OH.

In some embodiments, each R^(a1) is independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(a1)are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹².

In some embodiments, each R^(b1) is independently hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl ofR^(b1) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹². In one variation, R^(b1) isindependently hydrogen or C₁₋₆ alkyl.

In some embodiments, each R^(c1) and R^(d1) is independently hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or3- to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and 3- to 8-memberedheterocyclyl of R^(c1) and R^(d1) are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹²; or R^(c1) andR^(d1) are taken together with the nitrogen atom to which they areattached to form a 4- to 8-membered heterocyclyl optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹². In onevariation, each R^(c1) and R^(d1) is independently hydrogen or C₁₋₆alkyl.

22 In some embodiments, each R^(e1) is independently C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to 8-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(e1) areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹². In one variation, R^(e1) is independently C₁₋₆ alkyl.

In some embodiments, each R^(f1) is independently hydrogen or C₁₋₆alkyl. In one variation, R^(f1) is hydrogen.

In some embodiments, each R¹² is independently oxo, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl, 3- to 6-memberedheterocyclyl, halogen, cyano, —C(O)R^(a2), —C(O)OR^(b2),—C(O)NR^(c2)R^(d2), —OR^(b2), —OC(O)R^(a2), —OC(O)NR^(c2)R^(d2),—S(O)₂R^(e2), —S(O)₂NR^(c2)R^(d2), —NR^(c2)R^(d2), —N(R^(f2))C(O)R^(a2),—N(R^(f2))C(O)OR^(b2), —N(R^(f2))C(O)NR^(c2)R^(d2),—N(R^(f2))S(O)₂R^(e2), or —N(R^(f2))S(O)₂NR^(c2)R^(d2); wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl and 3- to6-membered heterocyclyl of R¹² are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹³.

In one variation, each R¹² is independently oxo, halogen, cyano,—OR^(b2), or C₁₋₆ alkyl optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³. In one variation, each R¹²is independently oxo, halogen, cyano, or hydroxyl.

In one variation, R¹² is C₁₋₆ alkyl optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹³.

In one variation, R¹² is oxo, hydroxyl, C₁₋₆ alkyl, or —O(C₁₋₆ alkyl).

In some embodiments, each R^(a2) is independently hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl or 3- to6-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl ofR^(a2) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³. In one variation, R^(a2) isindependently hydrogen or C₁₋₆ alkyl.

In some embodiments, each R^(b2) is independently hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl or 3- to 6-membered heterocyclyl; wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl and 3- to 6-membered heterocyclyl of R^(b2) areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³. In one variation, R^(b2) is hydrogen.

In some embodiments, each R^(c2) and R*² is independently hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl or 3- to 8-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₆ cycloalkyl and 3- to 8-membered heterocyclyl of R^(c2)and R^(d2) are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³; or R^(c2) and R^(d2) aretaken together with the nitrogen atom to which they are attached to forma 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³. In one variation, eachR^(c2) and R^(d2) is independently hydrogen or C₁₋₆ alkyl.

In some embodiments, each R^(e2) is independently C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl or 3- to 6-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to6-membered heteroaryl and 3- to 6-membered heterocyclyl of R^(e2) areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³. In one variation, R^(e2) is independently C₁₋₆ alkyl.

In some embodiments, each R^(f2) is independently hydrogen or C₁₋₆alkyl. In one variation, R^(f2) is hydrogen.

In some embodiments, each R¹³ is independently oxo, halogen, hydroxyl,—O(C₁₋₆ alkyl), cyano, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In one variation, each R¹³ is independently halogen, hydroxyl, —O(C₁₋₆alkyl), cyano, or C₁₋₆ alkyl.

In one variation, R¹³ is oxo, hydroxyl, C₁₋₆ alkyl, or —O(C₁₋₆ alkyl).

Representative compounds are listed in Table 1. It is understood thatindividual enantiomers and diastereomers are included in the table belowby Compound No. and Compound Name, and their corresponding structurescan be readily determined therefrom. In some instances, the enantiomersor diastereomers are identified by their respective properties, forexample, retention times on a chiral HPLC or its biological activities,and the absolute stereo configurations of the chiral centers arearbitrarily assigned.

TABLE 1 No. Structure Name 101

N-[4-[[3-[2-[(4- aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-methyl-phenyl]-2- chloro-benzenesulfonamide 102

N-[4-[[3-[2-[(4- aminocylcohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-fluoro-5-methyl- phenyl]-2-chloro-benzenesulfonamide103

(S)-N-((2-chlorophenyl)sulfonyl)-4- methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)benzamide 104

N-[4-[[3-[2-[(4- aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-chloro-5-fluoro- phenyl]-2-chloro-benzenesulfonamide105

(S)-3,3,3-trifluoro-N-(2-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamide 106

(S)-N-(2-fluoro-4-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 107

(S)-N-(2,5-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 108

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 109

(S)-N-(2,5-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3,3,3-trifluoropropane-1- sulfonamide 110

(S)-N-(2,5-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3,3,3-trifluoropropane-1- sulfonamide 111

N-(2,3-difluoro-4-((3-(2-(((3S,5R)-5-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide 112

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropipeiridn-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide 113

(S)-1-phenyl-N-(4-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2- (trifluoromethyl)phenyl)methanesulfona- mide 114

(S)-2-chloro-N-(3-fluoro-5-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamide 115

(S)-N-(3-fluoro-5-methyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)butane-1- sulfonamide 116

(S)-N-(3-fluoro-5-methyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)cyclopentanesulfonamide 117

(S)-N-(3-fluoro-5-methyl-4-((3-(2- (piperidin-3-ylamino)pyrimidi-4-yl)pyridin-2- yl)oxy)phenyl)cyclohexanesulfonamide 118

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-fluoro-5- methylphenyl)propane-1-sulfonamide 119

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-fluoro-5- methylphenyl)-1-phenylmethanesulfonamide 120

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-fluoro-5- methylphenyl)cyclopropanecarboxamide121

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-chloro-5- fluorophenyl)propane-1-sulfonamide 122

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3,5- difluorophenyl)propane-1-sulfonamide 123

(S)-2-Chloro-N-(2,3-dimethyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 124

(S)-N-(2,5-Dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)propane-1-sulfonamide125

(S)-2-chloro-N-(2,5-dimethyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 126

(S)-N-(2,5-Dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)propane-1-sulfonamide127

(S)-N-(4-fluoro-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamide 128

(S)-2-Chloro-N-(4-fluoro-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamdie 129

(S)-2-Cyclohexyl-N-(2,3-dimethyl-4-((3-(2-(piperiidn-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)acetamide 130

(S)-2-(4-Chlorophenyl)-N-(2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)acetamide 131

(S)-2-chloro-N-(3,5-dimethyl-4-((3-(2- (piperidin-3-ylamino)pyrimiin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 132

(S)-2-chloro-N-(3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamide 133

(S)-1-phenyl-N-(3-((3-(2-(piperidin-3- ylamino)pyrimidi-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 134

(S)-2-chloro-N-(4-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfoanmdie 135

(S)-2-chloro-N-(4-methyl-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 136

(S)-N-(4-methyl-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethaensulfonamide 137

(S)-2-chloro-N-(4-chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamide 138

(S)-N-(4-chloro-2-fluoro-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 139

(S)-2-chloro-N-(2-methyl-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 140

(S)-N-(2-methyl-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 141

(S)-2-chloro-N-(2-fluoro-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 142

(S)-N-(2-fluoro-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 143

(S)-N-(4-chloro-2-fluoro-3-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1- sulfonamide 144

(S)-N-(2-fluoro-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamide 145

(S)-1-cyclohexyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 146

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamide 147

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)cyclopropanecarboxamide148

(S)-N-(2,3-Difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-2,2-difluorobutane-1-sulfonamide 149

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3,3-difluorobutane-1-sulfonamide 150

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)spiro[2.2]pentane-1-carboxamide 151

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)spiro[2.2]pentane-1-carboxamide 152

(S)-N-(2,6-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 153

(S)-1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 154

(S)-N-(2,6-difluoro-3-methyl-4-(3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)(phenyl)methanesulfonamide 155

(S)-N-(2,3-difluoro-5-methyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 156

(S)-1-phenyl-N-(2,3,5-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 157

(S)-N-(3-methyl-4-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 158

(S)-N-(2-fluoro-5-methyl-4-(3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)(phenyl)methanesulfonamide 159

(S)-N-(3-fluoro-4-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 160

(S)-N-(2,3-difluoro-6-methyl-4-((3-(2- (piperiidn-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 161

(S)-N-(2-chloro-3-fluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 162

N-(2,3-difluoro-4-((3-(2-(((3S,5R)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 163

(S)-N-(2-cyano-3-fluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 164

N-(2,6-difluoro-3-methyl-4-((3-(2-(((3S, 5R)-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide 165

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5R)-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)methanesulfonamide166

(S)-1-(4-cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 167

(S)-N-(2,3-difluoro-4-((3-(2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 168

N-(2,3-difluoro-4-((3-(2-((1- methylpiperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 169

N-(4-((3-(2-(((1r,4r)-4- aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3-difluorophenyl)- 1-phenylmethanesulfonamide 170

(S)-N-(2,3-difluoro-4-((3-(2-((1-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide 171

N-(4-((3-(2-((2- aminoethyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3-difluorophenyl)- 1-phenylmethanesulfonamide 172

N-(2,3-difluoro-4-((3-(2-(2- (methylamino)ethylamino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl- methanesulfonamide 173

(S)-1-cyclobutyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 174

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-phenylmethanesulfonamide 175

(S)-N-(6-fluoro-2,3-dimethyl-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 176

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 177

N-(2,3-difluoro-5-methyl-4-((3-(2- (((3S,5R)-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide 178

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)-5-methyl-phenyl)-1- phenyl-methanesulfonamide 179

N-(2,6-difluoro-4-((3-(2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)-3-methyl-phenyl)-1- phenyl-methanesulfonamide 180

N-(2,3-difluoro-4-((3-(2-(4- piperidylamino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl- methanesulfonamide 181

(S)-N-(2,3-difluoro-4-((3-(2-((6- oxopiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1- phenylmethanesulfonamide 182

N-(2,3-difluoro-4-((3-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide 183

(S)-N-(4-((3-(2-((5,5-difluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3-difluorophenyl)-1-phenylmethanesulfonamide 184

N-(4-((3-(2-((2- (dimethylamino)ethyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3- difluorophenyl)-1- phenylmethanesulfonamide185 186

N-(4-((3-(2-(3-azabicyclo[3.1.0]hexan-5-ylamino)pyrimidin-4-yl)-2-pyridyl)oxy)- 2,3-difluoro-phenyl)-1-phenyl-methanesulfonamide 187

(S)-1-(2-cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 188

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(1-fluorocyclopropyl)methanesulfonamide 189

2,2-difluoro-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)butane-1-sulfonamide 190

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoro-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)methanesulfonamide191

1-(4-cyanophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 192

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2,2-difluorocyclobutyl)methanesulfonamide 193

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3R,5R)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)methanesulfonamide194

(S)-2,2-difluoro-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)butane-1- sulfonamide 195

(S)-1-(5-methylisoxazol-3-yl)-N-(2,3,6- trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 196

(S)-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(6-(trifluoromethyl)pyridin-3- yl)methanesulfonamide 197

(S)-N-(2-fluoro-3-((3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)benzyl)cyclopropanecarboxamide 198 199

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (piperidin-3-ylmethyl)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 200 201

1,1,1-trifluoro-3-((2-fluoro-3-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol 202

1-cyclobutyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 203

1-(5-methylisoxazol-3-yl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 204

1-(5-methylisoxazol-3-yl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 205

3,3,3-trifluoro-N-(2,3,6-trifluoro-4-((3- (2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2- pyridyl)oxy)phenyl)propane-1-sulfonamide 206

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3,5-difluorobenzenesulfonamide 207

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- y)oxy)phenyl)-3-(trifluoromethoxy)benzenesulfonamide 208

(S)-N-(2,3-difluoro-4-((3-(2-(piperiidn-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3-(difluoromethoxy)benzenesulfonamide 209

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(spiro[3.3]heptan-2-yl)methanesulfonamide 210

(S)-3-cyano-N-(2,3-difluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3- methylbutane-1-sulfonamide 211

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-4-methoxybenzenesulfonamide 212

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3-methoxybenzenesulfonamide 213

(S)-1-(4-chlorophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin- 4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 214

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)pyridine-3-sulfonamide215

(S)-2-cyclohexyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1- sulfonamide 216

(S)-3-cyano-N-(2,3-difluoro-4-((3-(2- (piperidine-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-2,2- dimethylpropane-1-sulfonamide 217

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-2-(2,2-difluorocyclopropyl)ethane-1- sulfonamide 218

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 219

(S)-4-cyano-N-(2,3-difluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 220

(S)-3-cyano-N-(2,3-difluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 221

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-methyl-1H-imidazole-4-sulfonamide 222

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide 223

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-4-(trifluoromethoxy)benzenesulfonamide 224

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-2-methoxybenzenesulfonamide 225

(S)-1-(3-chlorophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin- 4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 226

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3,3-dimethylbutane-1-sulfonamide 227

(S)-2-chloro-N-(2,3-difluoro-4-((3-(2- (piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)benzenesulfonamide 228

(S)-1-cyclopentyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 229

(S)-1-(3-cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 230

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-4,4-dimethylpentane-1-sulfonamide 231

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(3-fluorophenyl)methanesulfonamide 232

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)-1-(3,3-difluorocyclobutyl)methanesulfonamide 233

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)-1-(pyridin-3-yl)methanesulfonamide 234

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)-1-(pyridin-4-yl)methanesulfonamide 235

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)-1-(4-fluorophenyl)methanesulfonamide 236

(S)-1-(1-methyl-1H-pyrazol-3-yl)-N-(2,3,6-trifluoro-4-(3-(2-(piperidin-3- ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)methanesulfonamide 237

N-[2-fluoro-3-methyl-4-[[3-[2-[[(3S)-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]-1phenylmethanesulfonamide 238

(S)-N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yloxy)phenyl)-1-(pyridin-2-yl)methanesulfonamide 239

1-(2-chlorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperiidn-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 240

1-(2-chloro-6-fluorophenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 241

1-(4-(difluoromethyl)phenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 242

1-(2-fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 243

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 244

1-(2-chloro-4-fluorophenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 245

1-(4-chlorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 246

1-(2,6-difluorophenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidn-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 247

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(6- (trifluoromethyl)pyridin-3-yl)methanesulfonamide 248 249

1-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-one 250

(S)-1-(4-cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 251

1-(3,3-difluorocyclobutyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 252

2-methoxy-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)ethane-1-sulfonamide253

3,3-difluoro-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)butane-1-sulfonamide254

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(6- (trifluoromethyl)pyridin-3-yl)methanesulfonamide 255

1-(4-cyanophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5- methylphenyl)methanesulfonamide 256

1-(pyridin-3-yl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 257

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 258

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)pyrrolidine- 1-sulfonamide 259

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5R)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 260

2,2,2-trifluoro-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamide hydrochloride 261

1-(1-fluorocyclopropyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 262

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 263

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)piperidine-1- sulfonamide 264 265

1-(2,2-difluorocyclobutyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 266

4-(2-(4-(dimethylsulfamoylamino)-2,3,5- trifluoro-phenoxy)-3-pyridyl)-2-(((3S,5S)-5-fluoro-3- piperidyl)amino)pyrimidine 267

2-cyclopropyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamide 268

2,2-difluoro-N-(2,3,6-trifluoro-4-((5-fluoro-3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)butane-1-sulfonamide269

4-(2-(4- ((ethyl(methyl)sulfamoyl)amino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)-2- (((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidine 270

2,2-difluoro-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)-6- methylpyridin-2-yl)oxy)phenyl)butane-1-sulfonamide 271

1-(2,2-difluorocyclopropyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 272

N-(4-((3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)pyrimi-din-4-yl)pyridin-2-yl)oxy)-2,3,6- trifluorophenyl)-1-phenylmethanesulfonamide hydrochloride 273 274

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamide 275

1-(2-fluorophenyl)-N-(2,3,6-trifluoro-4- ((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 276

1-(4-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea 277 278

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5- (fluroomethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 279

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-6-methylphenyl)-1-phenylmethanesulfonamide 280

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidn-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methylphenyl)-1- phenylmethanesulfonamide 281

1-(2,4-difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5- methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 282

1-(2,6-difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5- methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 283

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-(2,6-difluorophenyl)methanesulfonamide 284

1-p-tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 285

1-(4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)urea hydrochloride 286

1-(3-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)urea hydrochloride 287 288

N-(4-((3-(2-((1-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide hydrochloride 290

1-o-tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 291

1-(3-methoxyphenyl)-N-(2,3,6-trifluoro- 4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-l)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 292

N-(2,6-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-3-methylphenyl)-1-phenylmethanesulfonamide 293

N-(2,6-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-methylphenyl)-1-(2,6-difluorophenyl)methanesulfonamide 294 295

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 296

N-(2-fluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methoxyphenyl)- 1-phenylmethanesulfonamide 297

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-5-methylphenyl)-1-(p-tolyl)methanesulfonamide 298 299 300 301

N-(4-((3-(2-((1,1-difluoro-5- azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide 302 303

N-(4-((3-(2-((5- (difluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide 304

1-(4-methoxyphenyl)-N-(2,3,6-trifluoro- 4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 305

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-6-methylphenyl)-1-(p-tolyl)methanesulfonamide 306 307 308

N-(4-((3-(2-((4-(dimethylamino)-3- fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6- trifluorophenyl)-1- phenylmethanesulfonamide309

N-(4-((3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)pyrimi-din-4-yl)pyridin-2-yl)oxy)-2,3,6- trifluorophenyl)propane-1-sulfonamide310

N-(4-((3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)pyrimi-din-4-yl)pyridin-2-yl)oxy)-2,3,6- trifluorophenyl)-3,3-difluorobutane-1-sulfonamide 311

N-(2,5-difluoro-4-((3-(2-(((3S,5S)-5- fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-3-methylphenyl)-1-(p-tolyl)methanesulfonamide 312

1-(4-(methylsulfonyl)phenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 313

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1- phenylethane-1-sulfonamidehydrochloride 314

N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1- phenylethane-1-sulfonamide 315

1-(4-cyclopropylphenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 316

1-(4-fluorophenyl)-N-(2,3,6-trifluoro-4- ((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 317 318 319

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin- 4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 320

1-(2,4-difluorophenyl)-N-(2,3,6-trifluoro- 4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 321

1-(4-cyanophenyl)-N-(2,3,6-trifluoro-4- ((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 322

1-(4-fluoro-2-methylphenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 323

N-(6-chloro-2,3-difluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamide 324 325 326 327

N-(4-((3-(2-((5-cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamide 328 329 330 331

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5- (methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 332

N-(3-chloro-2,6-difluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamide 333

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide hydrochloride 334 335 336

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 337

N-(4-((3-(2-((5-(1,1- difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamdie hydrochloride 338 339

N-(4-((3-(2-((5-(1,1- difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide 340

N-(5-chloro-2,3-difluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamide 341

1-(4-fluorophenyl)-N-(2,3,6-trifluoro-4- ((3-(2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl) amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide hydrochloride 342 343 344 345

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5- (1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamidehydrochloride 346 347 348 349

1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5- (1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 350

N-(2,3,6-trifluoro-4-((3-(2-(((1r,4r)-4- ((2-methoxyethyl)(methyl)amino)cyclohexyl) amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide 351

1-(2,4-difluorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamide 352

1-(2-chlorophenyl)-N-[2,3,6-trifluoro-4- [[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide353

1-(3-chlorophenyl)-N-[2,3,6-trifluoro-4- [[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide354

1-(4-chlorophenyl)-N-[2,3,6-trifluroo-4- [[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide355

1-(2-fluorophenyl)-N-[2,3,6-trifluoro-4- [[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide356

1-(2-pyridyl)-N-[2,3,6-trifluoro-4-[[3-[2- [[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide357

1-(2-cyano-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide358

1-(2-cyanophenyl)-N-[2,3,6-trifluoro-4- [[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide359

1-(4-pyridyl)-N-[2,3,6-trifluoro-4-[[3-[2- [[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide360

1-(4-cyano-2-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide361

3-fluoro-4-[[2,3,6-trifluoro-4-[[3-[2- [[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]sulfamoyl-methyl]benzamide 362

1-(4-chloro-2-cyano-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide363

1-(2,6-difluorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamide 364

1-(4-chloro-2-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide365

1-(2-chloro-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide366

1-(3-chloro-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methanesulfonamide367

1-(2-chloro-6-fluorophenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 368

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide 369

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)cyclopentanesulfonamide 370

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(4-(trifluoromethyl)phenyl)methanesulfona- mide 371

1-(4-(difluoromethyl)phenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 372

1-(4-fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 373

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)phenyl)methanesulfona- mide 374

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(3-(trifluoromethyl)phenyl)methanesulfona- mide 375

1-p-tolyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 376

1-(bicyclo[2.2.1]heptan-1-yl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 377

1-(bicyclo[2.2.2]octan-1-yl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 378

1-(2,5-difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 379

1-(4-cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1- sulfonamide 380

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-1-(2-methoxyphenyl)methanesulfonamide 381

(S)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)-9H-fluorene-9-sulfonamide 382

N-(4-((3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)pyrimi-din-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-3,3,3-trifluoropropane- 1-sulfonamide 383

1-m-tolyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 384

1-(2-fluoro-4-methylphenyl)-N-(2,3,6- trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4- yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide 385

1-(3-methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 386

1-o-tolyl-N-(2,3,6-trifluoro-4-((3-(2- (((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)phenyl)methanesulfonamide 387

(*S)-1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)ppyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamide 388

(*R)-1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3- yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamide 389

N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2- (trifluoromethyl)pyridin-3-yl)methanesulfonamide *arbitrarily assigned

In some embodiments, provided is a compound selected from Compound Nos.101-389 in Table 1, or a pharmaceutically acceptable salt thereof. Insome embodiments, provided is a compound selected from Compound Nos.101-238 or 248-389 in Table 1, or a pharmaceutically acceptable saltthereof.

Preparation of Formula I Compounds

Formula I compounds can be synthesized by synthetic routes that includeprocesses analogous to those well-known in the chemical arts,particularly in light of the description contained herein, and those forother heterocycles described in: Comprehensive Heterocyclic ChemistryII, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; LiebigsAnnalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990),each of which are expressly incorporated by reference. Startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley,N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4,Aufl. ed. Springer-Veriag, Berlin, including supplements (also availablevia the Beilstein online database). Formula I compounds can also be madefollowing the procedures found in U.S. Pat. Nos. 8,476,434, 7,880,000,WO 2005/113494, U.S. Pat. No. 7,868,177, and WO 2007/100646.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing Formula I compoundsand necessary reagents and intermediates include, for example, thosedescribed in R. Larock, Comprehensive Organic Transformations, VCHPublishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley and Sons (1999); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

Compounds of Formula I can be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I can be prepared by acombinatorial split and mix approach or by multiple parallel synthesesusing, for example, either solution phase or solid phase chemistry. Thusaccording to a further aspect provided herein is a compound librarycomprising at least 2 compounds, or pharmaceutically acceptable saltsthereof as described herein.

The Examples provide exemplary methods for preparing Formula Icompounds. Those skilled in the art will appreciate that other syntheticroutes can be used to synthesize the Formula I compounds. Althoughspecific starting materials and reagents are depicted and discussed inthe Examples, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the exemplary compounds prepared by thedescribed methods can be further modified in light of this disclosureusing conventional chemistry.

In preparing compounds of Formula I, protection of remote functionality(e.g., primary or secondary amine) of intermediates can be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection canbe readily determined. For a general description of protecting groupsand their use, see T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991.

In the methods of preparing Formula I compounds, it can be advantageousto separate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified to the desired degree of homogeneity by thetechniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods such as by chromatography and/or fractional crystallization.Enantiomers can be separated by converting the enantiomeric mixture intoa diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., chiral auxiliary such as a chiral alcohol orMosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereoisomers to the correspondingpure enantiomers. Also, some of the compounds or pharmaceuticallyacceptable salts thereof described herein can be atropisomers (e.g.,substituted biaryls). Enantiomers can also be separated by use of achiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer can be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds or pharmaceutically acceptable salts thereof described hereincan be separated and isolated by any suitable method, including: (1)formation of ionic, diastereomeric salts with chiral compounds andseparation by fractional crystallization or other methods, (2) formationof diastereomeric compounds with chiral derivatizing reagents,separation of the diastereomers, and conversion to the purestereoisomers, and (3) separation of the substantially pure or enrichedstereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts can be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Compounds of Formula (I) can be prepared by procedures in the Examples,the General Procedures, and generally by Schemes 1-4, where R groups areas described herein,

Scheme 1 shows coupling of a (2-halopyridin-3-yl)boronic acid or estercompound A (R═H, C₁-C₆ alkyl, pinacol; X¹=halogen) with a4-chloro-2-(methylthio)pyrimidine compound B (R═C₁-C₆ alkyl, X²=halogen)under palladium catalysis to form4-(2-halopyridin-3-yl)-2-(alkylthio)pyrimidine compound C.

Scheme 2 shows coupling of a phenol compound D with a4-(2-halopyridin-3-yl)-2-(alkylthio)pyrimidine compound C to form a4-(2-(phenyloxy)pyridin-3-yl)pyrimidine-2-alkylthiol E compound.Oxidation of the sulfur atom forms2-(alkylsulfinyl)-4-(2-(phenyloxy)pyridin-3-yl)pyrimidine compound F.The sulfoxide is displaced with a primary amine (R¹—NH₂) to form aFormula I or I′ compound, or an intermediate to be converted to aFormula I or I′ compound.

Scheme 3 shows an alternative route to Formula I compounds where a4-(2-halopyridin-3-yl)-2-(alkylthio)pyrimidine compound C is oxidized toa 4-(2-halopyridin-3-yl)-2-(alkylsulfinyl)pyrimidine compound H. Thesulfoxide is displaced with a primary amine (R¹—NH₂) to form a4-(2-halopyridin-3-yl)-I-alkylpyrimidin-2-amine compound I. Coupling ofcompound I with a phenol compound D forms a Formula I compound, or anintermediate to be converted to a Formula I compound.

Scheme 4 shows the general preparation of exemplary compounds fromaniline intermediate, tert-butyl(S)-3-((4-(2-(4-amino-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate.The aniline intermediate is treated with a carboxlic acid (R^(a)COOH)and a coupling reagent, such as1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) as in General Procedure C, oralternatively with an acid chloride (R^(a)COCl) and an amine base suchas diisopropylethylamine (DIPEA) or pyridine, to form Boc-protected,amide intermediates (top). The aniline intermediate is treated with asulfonyl chloride (R^(b)SO₂Cl) and an amine base to form Boc-protected,sulfonamide intermediates (middle) as in General Procedure A. TheBoc-protected intermediates are deprotected with acid, such ashydrochloric acid as in General Procedure B, to form exemplarycompounds, such as those in Table 1 and the Examples.

The following General Procedures illustrate synthetic reactions andoperations useful to prepare certain Example compounds (Table A1). Thereagents, solvents, amounts, equivalents, and conditions areillustrative and exemplary, and not meant to be limiting.

General Procedure A—Sulfonamide Synthesis

To a solution of the aniline (1.0 equiv) in pyridine (5 mL/mmol) and asolvent such as dichloromethane (DCM) at 0° C. or room temperature (rt)was added the corresponding sulfonyl chloride (1.2 equiv typicallyotherwise noted). After the addition was completed, the reactionsolution was stirred at rt for about 16 h. Water (10 mL) was added. Themixture was extracted with DCM. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo.

General Procedure B—Boc Deprotection

To a mixture of the tert-butyl-carbamate (Boc) intermediate (100 mg,0.16 mmol) in DCM (25 mL/mmol) or EtOAc was added hydrochloric acid (4 Min dioxane, 10 mL/mmol). The mixture was then stirred at rt for 1 h andconcentrated in vacuo or the resulting HCl salt was isolated byfiltration.

General Procedure C—Amide Coupling Using Carboxylic Acids

To a solution of the aniline intermediate (1.05 equiv otherwiseindicated) and DIPEA (3.0 equiv otherwise indicated) in DCM (16 mL/mmolotherwise indicated) was added HATU (2.0 equiv otherwise indicated). Themixture was stirred at rt for 0.5 h. The acid (1.0 equiv otherwiseindicated) was added and the resulting mixture was refluxed overnight.The mixture was diluted in DCM, washed with water and brine, dried (Mianhydrous sodium sulfate, and concentrated in vacuo. Alternatively, to asolution of the aniline in CH₂Cl₂ was added the acid chloride followedby addition of (iPr)₂NEt or Et₃N or pyridine and stirring at rt.Alternatively, to a solution of the aniline in DMF was added thecarboxylic acid and HATU followed by addition of (iPr)₂NEt or Et₃N andstirring at rt. Other coupling reagents can be used in General ProcedureC. The crude product was isolated and purified using known methods or asdescribed in the Examples.

General Procedure D—Cbz Deprotection

A mixture of benzyl-carbamate, palladium on carbon (Pd/C) and ammoniumformate in iPrOH was heated at 60° C. When complete, the mixture wasfiltered through celite using MeOH/CH₂Cl₂ and concentrated in vacuo.

Analytical Methods:

LCMS (Liquid Chromatography Mass Spectrometry) methods to separate andcharacterize the exemplary compounds are performed on one or more of thefollowing:

SHIMADZU LC-MS 2010EV coupled with SHIMADZU LC20AB using ESI asionization source. The LC separation was using Column: MERCK, RP-18e25-2 mm; Detector: PDA, ELSD; Wavelength: UV 220 nm; Column temperature:50° C.; mobile Phase: 1.5 mL/4 LTFA in water (solvent A) and 0.75 mL/4 LTFA in acetonitrile (solvent B), using the elution gradient 5%-95%(solvent B) over 0.7 minutes and holding at 95% for 0.4 minutes at aflow rate of 1.5 mL/min;

SHIMADZU LC-MS 2010EV coupled with SHIMADZU LC20AB using ESI asionization source. The LC separation was using Column: MERCK, RP-18e25-2 mm; Detector: PDA, ELSD; Wavelength: UV 220 nm; Column temperature:50° C.; mobile Phase: 1.5 mL/4 L TFA in water (solvent A) and 0.75 mL/4L TFA in acetonitrile (solvent B), using the elution gradient 5%-95%(solvent B) over 0.7 minutes and holding at 95% for 0.4 minutes at aflow rate of 1.5 mL/min;

Agilent 1200 Series coupled with 6110 Quadrupole mass spectrometer,using ESI as ionization source. The LC separation was using Column:Xtimate C18 2.1×30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature:50° C.; Detector: PDA&ELSD. mobile Phase: 1.5 mL/4 L TFA in water(solvent A) and 0.75 mL/4 LTFA in acetonitrile (solvent B), using theelution gradient 10%-80% (solvent B) over 0.9 minutes and holding at 80%for 0.6 minutes at a flow rate of 1.2 mL/min.

SHIMADZU 2020 HPLC coupled with SHIMADZU MSD mass spectrometer using ESIas ionization source. The LC separation was using an Shim-PackXR-ODS-C18, 50×3.0 mm column with a 1 ml/minute flow rate. Solvent A iswater with 0.05% TFA and solvent B is acetonitrile with 0.05% TFA. Thegradient consisted with 5-100% solvent B over 2.2 minutes and hold 100%B for 1 minute. LC column temperature is 40° C. UV absorbance wascollected from 190 nm to 400 nm and mass spec full scan was applied toall experiments.

SHIMADZU 2020 HPLC coupled with SHIMADZU MSD mass spectrometer using ESIas ionization source. The LC separation was using an Gemini-NX 3μ C18110A, 50×3.0 mm column with a 1.2 ml/minute flow rate. Solvent A iswater with 0.4% NH₄HCO₃ and solvent B is acetonitrile. The gradientconsisted with 10-50% solvent B over 4 minutes and hold 50% B for 1.2minutes. LC column temperature is 40° C. UV absorbance was collectedfrom 190 nm to 400 nm and mass spec full scan was applied to allexperiments.

SHIMADZU UFLC-MS 2010EV coupled with SHIMADZU MSD mass spectrometerusing ESI as ionization source. The LC separation was using a Shim-packXR-ODS-C18, 50×3.0 mm column with a 1 ml/minute flow rate. Solvent A iswater with 0.05% TFA and solvent B is acetonitrile with 0.05% TFA. Thegradient consisted with 5-100% solvent B over 2.2 minutes and hold 100%B for 1 minute. LC column temperature is 40° C. UV absorbance wascollected from 190 nm to 400 nm and mass spec full scan was applied toall experiments.

Waters Alliance 2695 HPLC with column heater coupled with Waters ZQ 2000mass spectrometer using ESI as ionization source (ES+, 100-1200 amu).The LC separation was using an XBridge C18, 3.5 μm, 4.6×30 mm column at25° C. with a 3.0 mL/minute flow rate. Solvent A is Milli-Q H2O+10 mMAmmonium Formate pH: 3.8, and solvent B is acetonitrile. The gradientconsisted of isocratic 5% solvent B for 0.2 min, 5% to 100% B in 1.8minutes; hold 100% B for 1 minute. LC column temperature is 25° C. UVabsorbance was collected from 195-320 nm using a Waters PDA 996 UVdetector and mass spec full scan was applied to all experiments.

Waters Alliance 2695 HPLC with column heater coupled with Waters ZQ 2000mass spectrometer using ESI as ionization source (ES+, 100-1200 amu).The LC separation was using an XBridge C18, 3.5 μm, 4.6×30 mm column at25° C. with a 3.0 mL/minute flow rate. Solvent A is Milli-Q H2O+10 mMAmmonium Bicarbonate pH: 10, and solvent B is acetonitrile. The gradientconsisted of isocratic 5% solvent B for 0.2 min, 5% to 100% B in 1.8minutes; hold 100% B for 1 minute. LC column temperature is 25° C. UVabsorbance was collected from 195-320 nm using a Waters PDA 996 UVdetector and mass spec full scan was applied to all experiments.

Biological Evaluation

The relative efficacies of Formula I compounds or pharmaceuticallyacceptable salts thereof as described herein as inhibitors of an enzymeactivity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC₅₀”. Determination of IC₅₀ values can beaccomplished using conventional techniques known in the art. In general,an IC₅₀ can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC₅₀ value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC₉₀, etc.

Inhibition of IRE1α RNase activity was determined in an enzyme assaythat measured cleavage of the XBP1 stem loop by autophosphorylated IRE1αThis assay format was chosen to ensure that inhibitors of either theIRE1α kinase or the RNase domains would be identified. Binding to theATP pocket and inhibition of IRE1α kinase activity are not necessarilyrequired to inhibit the RNase activity. Compounds were also profiled incellular assays by direct measurement of XBP1s (B-DNA assay) or byquantification of the luciferase signal in HT1080 XBP1-Luc, whichcarries a luciferase fusion that is only in frame and expressed from thespliced XBP1 transcript In the IRE1α enzyme and XPBl-Luc assays,phenoxy-pyridyl-pyrimidine compounds described herein (e.g., compoundsin Table A1) demonstrated activity.

Cell proliferation, cytotoxicity, and cell viability of the Formula Icompounds including pharmaceutically acceptable salts thereof can bemeasured by the CellTiter-Glo®Luminescent Cell Viability Assay (PromegaCorp.). The CellTiter-Glo® Luminescent Cell Viability Assay is ahomogeneous method of determining the number of viable cells in culturebased on quantitation of the ATP present, an indicator of metabolicallyactive cells. The CellTiter-Glo® Assay is designed for use withmultiwell formats, making it ideal for automated high-throughputscreening (HTS), cell proliferation and cytotoxicity assays. Thehomogeneous assay procedure involves adding the single reagent(CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

Biological activity of Formula I compounds and pharmaceuticallyacceptable salts thereof was measured by an IRE1 biochemical bindingassay (Example B1), a biochemical RNase assay (Example B2), a cellularPD assay, XBP1s-LUC reporter (Example B3), and an IRE1α-based inhibitionof multiple myeloma (MM) cell proliferation assay.

Administration of Compounds

Compounds described herein can be administered by any route appropriateto the condition to be treated. Suitable routes include oral, parenteral(including subcutaneous, intramuscular, intravenous, intraarterial,intradermal, intrathecal and epidural), transdermal, rectal, nasal,topical (including buccal and sublingual), vaginal, intraperitoneal,intrapulmonary and intranasal. For local immunosuppressive treatment,the compounds can be administered by intralesional administration,including perfusing or otherwise contacting the graft with the inhibitorbefore transplantation. It will be appreciated that the preferred routecan vary with for example the condition of the recipient. Where thecompound is administered orally, it can be formulated as a pill,capsule, tablet, etc. with a pharmaceutically acceptable carrier orexcipient. Where the compound is administered parenterally, it can beformulated with a pharmaceutically acceptable parenteral vehicle and ina unit dosage injectable form, as detailed below.

Thus, in one aspect provided herein is a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt thereof asdescribed herein and one or more pharmaceutically acceptable excipients.In one embodiment, compounds described herein are administered aspharmaceutical compositions capable of being administered to a subjectorally or parenterally. The compounds described herein can be formulatedfor topical or parenteral use where the compound is dissolved orotherwise suspended in a solution suitable for injections, suspensions,syrups, creams, ointments, gels, sprays, solutions and emulsions.

Oral administration can promote patient compliance in taking thecompound (e.g. formulated as a pharmaceutical composition), therebyincreasing compliance and efficacy. Oral pharmaceutical compositionscomprising a compound described herein include, but are not limited to,tablets (e.g. coated, non-coated and chewable) and capsules (e.g. hardgelatin capsules, soft gelatin capsules, enteric coated capsules, andsustained release capsules). Tablets can be prepared by directcompression, by wet granulation, or by diy granulation. Oralpharmaceutical compositions comprising a compound described herein canbe formulated for delayed or prolonged release.

A dose to treat human patients can range from about 10 mg to about 1000mg of Formula I compound. A typical dose can be about 100 mg to about300 mg of the compound. A dose can be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors can influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet can beingested daily or less frequently for a specified period of time. Theregimen can be repeated for a number of cycles of therapy.

Methods of Treatment

In one aspect provided herein, Formula I compounds or pharmaceuticallyacceptable salts thereof are useful for treating a patient sufferingfrom a disease or disorder arising from abnormal cell growth, functionor behavior associated with the UPR pathway such as cancer, an immunedisorder, cardiovascular disease, viral infection, inflammation, ametabolism/endocrine disorder or a neurological disorder, can thus betreated by a method comprising the administration thereto of a compoundor pharmaceutically acceptable salts thereof described herein as definedabove. Thus, provided herein are methods of treating cancer byadministering to a patient having cancer an effective amount of acompound or pharmaceutically acceptable salt thereof described herein.The condition of the patient can thereby be improved or ameliorated.

The methods provided herein include treatment of solid tumors/cancers.For example, administration of a compound or pharmaceutically acceptablesalt thereof described herein can be performed for patients havingbreast cancer, ovary cancer, cervix cancer, prostate cancer, testiscancer, genitourinary tract cancer, esophagus cancer, larynx cancer,glioblastoma, neuroblastoma, stomach cancer, skin cancer,keratoacanthoma, lung cancer, epidermoid carcinoma, large cell cancer,non-small cell lung cancer (NSCLC), small cell carcinoma, lungadenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer,adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladdercarcinoma, liver carcinoma and biliary passages, kidney carcinoma,buccal cavity cancer, naso-pharyngeal cancer, pharynx cancer, lipcancer, tongue cancer, mouth cancer, small intestine cancer,colon-rectum cancer, large intestine cancer, rectum cancer, bronchialcancer, hepatocellular cancer, gastric cancer, endometrial cancer,melanoma, renal cancer, urinary bladder cancer, uterine corpus cancer,and uterine cervix cancer.

In another embodiment, the methods provided herein include treatment ofcancer by administering to a patient having cancer an effective amountof a compound or pharmaceutically acceptable salt thereof where thecancer comprises squamous cell carcinoma, small-cell lung cancer,non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous celllung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer,gastrointestinal cancer, esophageal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial cancer, uterine cancer, salivary gland carcinoma, renalcancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellularcarcinoma (HCC), anal carcinoma, penile carcinoma, or head and neckcancer.

In certain embodiments, the cancer is breast cancer. The breast cancercan be Stage I, II, III, or IV as understood in the art. In oneembodiment, the breast cancer is triple negative breast cancer (TNBC).In another embodiment, the breast cancer is Her2 negative breast cancer.

In another aspect provided herein are methods of treating hematologicalcancers such as, for example, lymphoma, lymphocytic leukemia (acute(ALL) and chronic (CLL), multiple myeloma (MM), acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), myelodysplasticsyndrome (MDS), myeloproliferative disease (MPD), or non-Hodgkinlymphoma In one embodiment, the methods herein include treatment oflymphoma lymphocytic leukemia multiple myeloma (MM), acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), myelodysplasticsyndrome (MDS), or myeloproliferative disease (MPD) by administering aneffective amount of a compound described herein.

In one embodiment, is a method of treating MM by administering to apatient having MM an effective amount of compound described herein.

In one aspect, provided is a method of treating an IRE1-related diseaseor disorder in a patient comprising administering an effective amount ofa compound of Formula (I) or pharmaceutically acceptable salt thereof,to a patient with an IRE1-related disease or condition. In anotheraspect, the method comprises administering to a patient with anIRE1-related disease or condition an effective amount of apharmaceutical composition comprising a compound of Formula (I) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carrier excipients. In some embodiments, thecompound is of the Formula I excluding compounds of Table 1X. In otherembodiments, the compound is of the Formula I including compounds ofTable 1X. In some embodiments, the compound is selected from Table 1, ora pharmaceutically acceptable salt thereof. In some embodiments, thepatient is a human patient.

In one embodiment, the cancer is an Ire 1-mediated cancer (i.e. a cancerhaving abnormal expression or activity of Ire 1 relative to a control).In me embodiment, the Ire1-mediated cancer has increased expression ofIre 1. In another embodiment, the Ire 1-mediated cancer has increasedactivity of Ire 1. Such increases can be measured against a control(e.g. against a patient having predetermined Ire1 function, expression,activity; or for example measure in a single patient before, during, orafter treatment with a compound or pharmaceutically acceptable saltthereof described herein).

In another aspect provided herein is a compound of Formula I or apharmaceutically acceptable salt thereof for use in a method fortreating an IRE1-related disease or disorder. In one aspect, provided isa use of a compound of Formula I or pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of anIRE1-related disease or disorder.

In some embodiments of the method of treating an IRE1-related disease ordisorder in a patient comprising administering an effective amount of acompound of Formula I or pharmaceutically acceptable salt thereof to apatient with an IRE1-related disease or condition, the method furthercomprising administering one or more additional therapeutic agent(s)selected from the group consisting of an anti-inflammatory agent, acorticosteroid, an immunomodulatory agent, anti-cancer agent asdescribed herein, an apoptosis-enhancer, a neurotropic factor, an agentfor treating cardiovascular disease, an agent for treating liverdisease, an anti-viral agent, an agent for treating blood disorders, anagent for treating diabetes, an agent for treating metabolic disorders,an agent for treating autoimmune disorders, an agent for treatingimmunodeficiency disorders, and combinations thereof. In someembodiments, the additional therapeutic agent is a corticosteroid, aproteasome inhibitor, an IMiD, an antibody, or a combination thereof. Insome embodiments, the additional therapeutic agent is a proteasomeinhibitor (e.g. carfilzomib, bortezomib, or ixazomib). In someembodiments, the additional therapeutic agent is an IMiD (e.g.lenalidomide or pomalidomide). In some embodiments, the additionaltherapeutic agent is an antibody (e.g., an anti-CD38 antibody, ananti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody oran anti-interleukin-6 antibody). In some embodiments, the additionaltherapeutic agent is a corticosteroid (e.g., dexamethasone). In someembodiments, the method further comprises radiotherapy.

Also provided herein is a method of treating a disease caused byabnormal levels of Ire1 activity in a human or animal patient in need ofsuch treatment with a Formula I compound or a pharmaceuticallyacceptable salt thereof described herein. The disease can be caused byan amount of Ire1 activity that is too low or too high. For example, thedisease can be caused by a deficiency in Ire1 activity or by abnormallyhigh Ire1 activity (e.g., hyperactivity of Ire1). The method includesadministering to the patient a effective amount of an Ire1 modulatorFormula I compound or a pharmaceutically acceptable salt thereofdescribed herein.

Ire1 deficiency is a decreased amount of Ire1 activity compared tonormal levels of Ire1 activity in a particular subject or a populationof healthy subjects. The decreased amount of Ire1 activity results inexcessive amounts of misfolded protein accumulation thereby causing thedisease state.

Ire1 hyperactivity is an increased amount of Ire1 activity compared tonormal levels of Ire1 activity in a particular subject or a populationof healthy subjects. The increased amount of Ire1 activity can resultin, for example, excessive amounts of cell proliferation thereby causingthe disease state.

In some embodiments, the disease is associated with Ire1 deficiency.Such diseases include, but are not limited to, cystic fibrosis,retinitis pigmentosa, diabetes, or a neurodegenerative disease. Theneurodegenerative disease can include Alexander's disease, Alper'sdisease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxiatelangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease). Bovine spongiformencephalopathy (BSF), Canavan disease, Cockayne syndrome, Corticobasaldegeneration, Creutzfeldt-Jakob disease, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy bodydementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, Narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoff s disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,Schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, or Tabes dorsalis.

In other embodiments, the disease is associated with abnormally highIre1. Such diseases include, but are not limited, to cancers,inflammatory diseases, and autoimmune diseases. Exemplary cancersinclude, but am not limited to, breast cancer and multiple myeloma. Inme embodiment, the disease is multiple myeloma. In (me embodiment, thedisease is a triple-negative breast cancer. Exemplary inflammatorydiseases include, but are not limited to, asthma, chronic inflammation,chronic prostatitis, glomerulonephritis, hypersensitivities,inflammatory bowel diseases, pelvic inflammatory disease; reperfusioninjury, rheumatoid arthritis, transplant rejection, and vasculitis.Exemplary autoimmune diseases include, but are not limited to,XBP1-linked Crohn's disease, Coeliac disease, diabetes mellitus type 1(IDDM), systemic lupus erythematosus (SLE), Sjogren's syndrome,Churg-Strauss Syndrome, Hashimoto's thyroiditis, Graves' disease,idiopathic thrombocytopenic purpura, and rheumatoid arthritis. In oneembodiment, the disease is XBP1-linked. Crohn's disease.

In one aspect provided herein is a method of treating atherosclerosis orthe progression of atherosclerosis by administering an effective amountof a compound or pharmaceutically acceptable salt thereof describedherein. In one embodiment, administration of a compound orpharmaceutically acceptable salt thereof described herein reduces thenumber of macrophages in an atherosclerotic lesion. Such reduction canbe imparted, in some embodiments, without altering apoptosis state. Inanother embodiment, administration of a compound or pharmaceuticallyacceptable salt thereof as described herein inhibits or reduces theproduction of IL-1β, CCL2, and chemokme receptor 2.

Pharmaceutical Formulations

Compounds or pharmaceutically acceptable salts thereof as describedherein can be formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition. Thus, further provided hereinis a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

A typical formulation is prepared by mixing a compound orpharmaceutically acceptable salt thereof as described herein and anexcipient. Suitable carriers, diluents and excipients include, but arenot limited to, materials such as carbohydrates, waxes, water solubleand/or swellable polymers, hydrophilic or hydrophobic materials,gelatin, oils, solvents, water and the like. The particular excipientused will depend upon the means and purpose for which the compound orpharmaceutically acceptable salt thereof as described herein is beingapplied. Solvents are generally selected based CHI solvents recognizedas safe (GRAS) to be administered to a mammal. In general, safe solventsare non-toxic aqueous solvents such as water and other non-toxicsolvents that are soluble or miscible in water. Suitable aqueoussolvents include water, ethanol, propylene glycol, polyethylene glycols(e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulationscan also include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents and otherknown additives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

The formulations can be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundor pharmaceutically acceptable salt thereof as described herein orstabilized form thereof (e.g., complex with a cyclodextrin derivative orother known complexation agent) is dissolved in a suitable solvent inthe presence of one or more of the excipients described above. Thecompound or pharmaceutically acceptable salt thereof as described hereinis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application can bepackaged in a variety of wav s depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers include materials such asbottles (plastic and glass), sachets, ampoules, plastic bags, metalcylinders, and the like. The container can also include a tamper-proofassemblage to prevent indiscreet access to the contents of the package.In addition, the container has deposited thereon a label that describesthe contents of the container. The label can also include appropriatewarnings.

Pharmaceutical formulations of the compounds or pharmaceuticallyacceptable salts thereof as described herein can be prepared for variousroutes and types of administration. For example, a compound orpharmaceutically acceptable salt thereof as described herein having thedesired degree of purity can optionally be mixed with one or morepharmaceutically acceptable excipients (Remington's PharmaceuticalSciences (1980) 16th edition, Osol, A Ed.), in the form of a lyophilizedformulation, milled powder, or an aqueous solution. Formulation can beconducted by mixing at ambient temperature at the appropriate pH, and atthe desired degree of purity, with physiologically acceptable carriers,i.e., carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but can range fromabout 3 to about 8. For example, formulation in an acetate buffer at pH5 can be a suitable embodiment.

The pharmaceutical composition ordinarily can be stored as a solidcomposition, a lyophilized formulation or as an aqueous solution.

The pharmaceutical compositions described herein can be formulated,dosed and administered in a fashion, i.e., amounts, concentrations,schedules, course, vehicles and route of administration, consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to ameliorate, or treat the hyperproliferativedisorder.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable pharmaceutically acceptable excipients are nontoxic torecipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients can also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds or pharmaceuticallyacceptable salts thereof as described herein may be prepared. Suitableexamples of sustained-release preparations include semi permeablematrices of solid hydrophobic polymers containing a compound orpharmaceutically acceptable salt thereof as described herein, whichmatrices are in the form of shaped articles, e.g., films, ormicrocapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers such as the LUPRON DEPOT™ (injectable microspherescomposed of lactic acid-glycolic acid copolymer and leuprolide acetate)and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any methods. Techniques andformulations generally are found in Remington's Pharmaceutical Sciences(Mack Publishing Co., Easton, Pa.). Such methods include the step ofbringing into association the active ingredient with the carrier whichconstitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of a compound or pharmaceutically acceptable salt thereofas described herein suitable for oral administration can be prepared asdiscrete units such as pills, capsules, cachets or tablets eachcontaining a predetermined amount of such compound or pharmaceuticallyacceptable salt thereof. Compressed tablets can be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets can be made by molding in a suitablemachine a mixture of the powdered active ingredient moistened with aninert liquid diluent The tablets can optionally be coated or scored andoptionally are formulated so as to provide slow or controlled release ofthe active ingredient therefrom. Tablets, troches, lozenges, aqueous oroil suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, e.g., gelatin capsules, syrups or elixirs can be preparedfor oral use. Formulations of compounds or pharmaceutically acceptablesalts thereof as described herein intended for oral use can be preparedaccording to any method for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientscan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs. The oily phase of the emulsions of compositions provided hereincan be constituted from known ingredients in a known manner. While thephase can comprise merely an emulsifier, it desirably comprises amixture of at least one emulsifier with a fat or an oil or with both afat and an oil. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat Together, theemulsifiers) with or without stabilizers) make up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. Emulsifiers and emulsion stabilizers suitablefor use in the formulation of described herein include Tween® 60, Span®80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerylmono-stearate and sodium lauryl sulfate.

Aqueous suspensions comprising compounds or pharmaceutically acceptablesalts thereof as described herein can contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds or pharmaceuticallyacceptable salts thereof as described herein can be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated using suitabledispersing or wetting agents and suspending agents which have beenmentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,3-butanediol orprepared as a lyophilized powder. Among the acceptable vehicles andsolvents that can be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration can be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers consideredto be appropriate.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The compounds or pharmaceutically acceptable salts thereof as describedherein can be used in veterinary compositions comprising at least oneactive ingredient as above defined together with a veterinary carrier.Veterinary carriers are materials useful for the purpose ofadministering the composition and can be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinaryfield and are compatible with the active ingredient. These veterinarycompositions can be administered parenterally, orally or by any otherdesired route.

Combination Therapy

The compounds of Formula I can be employed alone or in combination withadditional therapeutic agents for the treatment of a disease or disorderdescribed herein, such as inflammation or a hyperproliferative disorder(e.g., cancer). In certain embodiments, a compound of Formula I or apharmaceutically acceptable salt thereof as described herein is combinedin a pharmaceutical combination formulation, or dosing regimen ascombination therapy, with an additional, second therapeutic compoundthat has anti-inflammatory or anti-hyperproliferative properties or thatis useful for treating an inflammation, immune-response disorder, orhyperproliferative disorder (e.g., cancer). The additional therapeuticcan be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTORinhibitor, an anti-inflammatory agent, an immunomodulatory agent,anti-cancer agent as described herein, an apoptosis-enhancer, aneurotropic factor, an agent for treating cardiovascular disease, anagent for treating liver disease, an anti-viral agent, an agent fortreating blood disorders, an agent for treating diabetes, and an agentfor treating immunodeficiency disorders. The second therapeutic agentcan be an NSAID anti-inflammatory agent. The second therapeutic agentcan be an anti-cancer agent as described herein. The second compound ofthe pharmaceutical combination formulation or dosing regimen preferablyhas complementary activities to the compound of Formula I such that theydo not adversely affect each other. Such compounds are suitably presentin combination in amounts that are effective for the purpose intended.In one embodiment, a composition provided herein comprises a compound ofFormula I, or a stereoisomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt thereof, in combination with atherapeutic agent such as an NSAID.

The combination therapy can be administered as a simultaneous orsequential regimen. When administered sequentially, the combination canbe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and can be lowered due to the combined action (synergy)of the newly identified agent and other therapeutic agents ortreatments.

The combination therapy can provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect can be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect can be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of therapy, a compound of Formula I or a orpharmaceutically acceptable salt thereof, can be combined with othertherapeutic, hormonal or antibody agents such as those described herein,as well as combined with surgical therapy and radiotherapy. Combinationtherapies provided herein thus comprise the administration of at leastone compound of Formula I or pharmaceutically acceptable salt thereof,and the use of at least one other cancer treatment method. The amountsof the compound(s) of Formula I or pharmaceutically acceptable saltsthereof described herein, and the other pharmaceutically activetherapeutic agent(s) and the relative timings of administration will beselected in order to achieve the desired combined therapeutic effect.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is used in combination with an aromataseinhibitor, a phosphoinositide 3-kinase (PI3K)/mTOR pathway inhibitor, aCDK 4/6 inhibitor, a HER-2 inhibitor, a SERM, a SERD, an EGFR inhibitor,a PD-1 inhibitor, poly ADP-ribose polymerase (PARP) inhibitor, a histonedeacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, anAKT inhibitor, chemotherapy, or any combination thereof.

In some embodiments, a pharmaceutical composition comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, isadministered in combination with a therapeutic agent selected frompaclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin,fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab(HERCEPTTN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech),pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene,vinorelbine, capecitabine, and ixabepilone.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is used in combination with hormone blockingtherapy, chemotherapy, radiation therapy, monoclonal antibodies, orcombinations thereof.

Metabolites of Compounds of Formula I

Also provided herein are in vivo metabolic products of compounds orpharmaceutically acceptable salts thereof as described herein. Suchproducts can result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, provided herein are compounds produced by a processcomprising contacting a compound or pharmaceutically acceptable saltthereof described herein with a mammal for a period of time sufficientto yield a metabolic product thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., 14C or 3H) isotope of a compound orpharmaceutically acceptable salt thereof as described herein,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies. The metaboliteproducts, so long as they are not otherwise found in vivo, are useful indiagnostic assays for therapeutic dosing of the compounds orpharmaceutically acceptable salts thereof described herein.

Articles of Manufacture

In another aspect provided herein is an article of manufacture, or kit,containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula I orpharmaceutically acceptable salt thereof. The kit can further comprise alabel or package insert on or associated with the container. Suitablecontainers include, for example, bottles, vials, syringes, blister pack,etc. The container can be formed from a variety of materials such asglass or plastic. The container can hold a compound of Formula I or aformulation thereof which is effective for treating the condition andcan have a sterile access port (for example, the container can be anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I or a pharmaceutically acceptablesalt thereof. The label or package insert indicates that the compositionis used for treating the condition of choice, such as cancer. Inaddition, the label or package insert can indicate that the patient tobe treated is one having a disorder such as a hyperproliferativedisorder, atherosclerosis, neurodegeneration, cardiac hypertrophy, pain,migraine or a neurotraumatic disease or event. In one embodiment, thelabel or package inserts indicates that the composition comprising acompound of Formula I or a pharmaceutically acceptable salt thereof canbe used to treat a disorder resulting from abnormal cell growth. In oneembodiment, the label or package inserts indicates that the compositioncomprising a compound of Formula I or a pharmaceutically acceptable saltthereof can be used to treat a disorder resulting from atherosclerosis.The label or package insert can also indicate that the composition canbe used to treat other disorders. Alternatively, or additionally, thearticle of manufacture can further comprise a second containercomprising a pharmaceutically acceptable buffer, such as bacteriostaticwater for injection (BWFI), phosphate-buffered saline, Ringer's solutionand dextrose solution. It can further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, and syringes.

The kit can further comprise directions for the administration of thecompound of Formula I or a pharmaceutically acceptable salt thereof and,if present, the second pharmaceutical formulation. For example, if thekit comprises a first composition comprising a compound of Formula I ora pharmaceutically acceptable salt thereof and a second pharmaceuticalformulation, the kit can further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I or a pharmaceutically acceptablesalt thereof, such as tablets or capsules. Such a kit preferablyincludes a number of unit dosages. Such kits can include a card havingthe dosages oriented in the order of their intended use. An example ofsuch a kit is a blister pack. Blister packs are well known in thepackaging industry and are widely used for packaging pharmaceutical unitdosage forms. If desired, a memory aid can be provided, for example inthe form of numbers, letters, or other markings or with a calendarinsert, designating the days in the treatment schedule in which thedosages can be administered.

According to one embodiment, a kit can comprise (a) a first containerwith a compound of Formula I or a pharmaceutically acceptable saltthereof contained therein; and optionally (b) a second container with asecond pharmaceutical formulation contained therein, wherein the secondpharmaceutical formulation comprises a second compound withanti-hyperproliferative activity. Alternatively, or additionally, thekit can further comprise a third container comprising apharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It can further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I or a pharmaceutically acceptable salt thereof and a secondtherapeutic agent, the kit can comprise a container for containing theseparate compositions such as a divided bottle or a divided foil packet,however, the separate compositions can also be contained within asingle, undivided container. Typically, the kit comprises directions forthe administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

EMBODIMENTS Embodiment 1: A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R⁰ is hydrogen or fluoro;

R¹ is C₃₋₁₂ cycloalkyl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —(C₁₋₆ alkylene)-(C₃-C₁₂ cycloalkyl), or —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), —(C₁₋₆ alkylene)-OR^(1c), or—(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C₁₋₆alkylene of R¹ are independently optionally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰;

each R^(1a), R^(1b) and R^(1c) is independently hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(1a) and R^(1b) are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

R^(2A) and R^(2B) are independently hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆haloalkyl);

R³ is hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆ haloalkyl);

R⁴ and R⁵ are independently hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR^(7A),—NR^(8A)R^(8B), —NR⁸C(O)R⁷, —NR⁸C(O)OR^(7A), —NR⁸C(O)NR^(8A)R^(8B),—NR⁸SO₂R⁹, —NR⁸SO₂NR^(8A)R^(8B), —NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹,—C(O)NR^(8A)R^(8B), —C(O)R⁷, —C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹,or —SO₂NR^(8A)R^(8B); wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroarylof R⁴ and R⁵ are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

n is 0, 1, 2, or 3;

each R⁶ is independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), —O(C₁₋₆ haloalkyl),—SO₂(C₁₋₆ alkyl) or —SO₂(C₁₋₆ haloalkyl);

each R⁷ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, 5- to 14-membered heteroaryl, or 3- to 12-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, 5-to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R⁷ andR^(7A) are optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰;

each R^(7A) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to12-membered heterocyclyl of R⁷ and R^(7A) are optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰;

each R⁸ is independently hydrogen or C₁-C₆ alkyl;

each R^(8A) is independently hydrogen or C₁-C₆ alkyl;

each R^(8B) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, and 3- to12-membered heterocyclyl of R^(8B) are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰;

each R^(8C) is independently hydrogen or C₁-C₆ alkyl;

each R⁹ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰; or,

each R⁹ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl are optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰;

each R¹⁰ is independently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to12-membered heterocyclyl, halogen, cyano, —C(O)R^(a), —C(O)OR^(b),—C(O)NR^(c)R^(d), —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —SR^(b),—S(O)R^(e), —S(O)₂R^(e), —S(O)(═NH)R^(e), —S(O)₂NR^(c)R^(d),—NR^(c)R^(d), —N(R^(f))C(O)R^(a), —N(R^(f))C(O)OR^(b),—N(R^(f))C(O)NR^(c)R^(d), —N(R^(f))S(O)₂R^(e),—N(R^(f))S(O)₂NR^(c)R^(d), —P(O)R^(g)R^(h), or —SiR^(i)R^(j)R^(k);wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and 3- to 14-memberedheterocyclyl of R¹⁰ are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(a) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 12-membered heterocyclyl of R^(a) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹¹;

-   -   each R^(b) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to        12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and 3- to        12-membered heterocyclyl of R^(b) are each optimally substituted        with 1, 2, 3 or 4 substituents independently selected from R¹¹;

each R^(c) and R^(d) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl ofR^(c) and R^(d) are each optimally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

-   -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a 4- to 12-membered heterocyclyl        optimally substituted with 1, 2, 3 or 4 substituents        independently selected from R¹¹;

each R^(e) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 12-membered heterocyclyl of R^(e) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹;

each R^(f) is independently hydrogen or C₁₋₆ alkyl;

each R^(g) and R^(h) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or—O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R^(g)and R^(h) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹;

-   -   or R^(g) and R^(h) are taken together with the phosphorus atom        to which they are attached to form a 4- to 12-membered        heterocyclyl optimally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹;

each R^(i), R^(j) and R^(k) is independently C₁₋₆ alkyl;

each R¹¹ is independently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to8-membered heterocyclyl, halogen, cyano, —C(O)R^(a1), —C(O)OR^(b1),—C(O)NR^(c1)R^(d1), —OR^(b1), —OC(O)R^(a1), —OC(O)NR^(c1)R^(d1),—SR^(b1), —S(O)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(c1)R^(d1),—NR^(c1)R^(d1), —N(R^(f1))C(O)R^(a1), —N(R^(f1))C(O)OR^(b1),—N(R^(f1))C(O)NR^(c1)R^(d1), —N(R^(f1))S(O)₂R^(e1),—N(R^(f1))S(O)₂NR^(c1)R^(d1), —P(O)R^(g1)R^(h1), or—SiR^(i1)R^(j1)R^(k1); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and3- to 14-membered heterocyclyl of R¹¹ are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²;

each R^(a1) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 8-membered heterocyclyl of R^(a1) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²;

each R^(b1) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to 8-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(b1) areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹²;

each R^(c1) and R^(d1) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to 8-memberedheterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(c1) andR^(d1) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹²;

-   -   or R^(c1) and R^(d1) are taken together with the nitrogen atom        to which they are attached to form a 4- to 8-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹²;

each R^(e1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 8-membered heterocyclyl of R^(e1) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹²;

each R^(f1) is independently hydrogen or C₁₋₆ alkyl;

each R^(g1) and R^(h1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl,or —O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(g1)and R^(h1) are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²;

-   -   or R^(g1) and R^(h1) are taken together with the phosphorus atom        to which they are attached to form a 4- to 8-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹²;

each R^(i1), R^(j1) and R^(k1) is independently C₁₋₆ alkyl;

each R¹² is independently oxo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5-to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano,—CfOIR^(a2), —C(O)OR^(b2), —C(O)NR^(c2)R^(d2), —OR^(a2), —OC(O)R^(a2),—OC(O)NR^(c2)R^(d2), —S(O)₂R^(e2), —S(O)₂NR^(c2)R^(d2), —NR^(c2)R^(d2),—N(R^(f2))C(O)R^(a2), —N(R^(f2))C(O)OR^(b2),—N(R^(f2))C(O)NR^(c2)R^(d2), —N(R^(f2))S(O)₂R^(e2),—N(R^(f2))S(O)₂NR^(c2)R^(d2), or —P(O)R^(g2)R^(h2); wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl and 3- to6-membered heterocyclyl of R¹² are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹³;

each R^(a2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-memberedheteroaryl and 3- to 6-membered heterocyclyl of R^(a2) are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R^(b2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or 3-to 6-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl and3- to 6-membered heterocyclyl of R^(b2) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹³;

each R^(c2) and R^(d2) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or 3- to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl,C₃₋₆ cycloalkyl and 3- to 8-membered heterocyclyl of R^(c2) and R^(d2)are each optionally substituted with 1, 2, 3 or 4 substituentindependently selected from R¹³;

-   -   or R^(c2) and R^(d2) are taken together with the nitrogen atom        to which they are attached to form a 4- to 6-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹³;

each R^(e2) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to6-membered heteroaryl or 3- to 6-membered heterocyclyl; wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl and 3- to6-membered heterocyclyl of R^(e2) are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹³;

each R^(f2) is independently hydrogen or C₁₋₆ alkyl;

each R^(g2) and R^(h2) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-to 8-membered heterocyclyl, or —O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and 3- to 8-membered heterocyclyl of R^(g2) and R^(h2)are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³;

-   -   or R^(g2) and R^(h2) are taken together with the phosphorus atom        to which they are attached to form a 4- to 6-membered        heterocyclyl optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹³; and

each R¹³ is independently oxo, halogen, hydroxyl, —O(C₁₋₆ alkyl), cyano,C₁₋₆ alkyl or C₁₋₆ haloalkyl;

provided that the compound is other than Compound Nos. 1x-12x in Table1X and salts thereof.

Embodiment 2: The compound of embodiment 1, wherein R^(2A) and R^(2B)are independently H, F, Cl or C₁-C₆ alkyl.

Embodiment 3: The compound of embodiment 2, wherein R^(2A) is H, F ormethyl, and R^(2B) is H, F, Cl or —CH₃.

Embodiment 4: The compound of any one of embodiments 1 to 3, wherein R³is H, F, Cl, —CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

Embodiment 5: The compound of embodiment 4, wherein R³ is H, F, Cl, —CN,—CH₃, or —CF₃.

Embodiment 6: The compound of any one of embodiments 1 to 5, wherein nis 0.

Embodiment 7: The compound of any one of embodiments 1 to 6, wherein R⁵is H, F, Cl, —CN, or C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰.

Embodiment 8: The compound of embodiment 7, wherein R⁵ is H, F, Cl, —CN,—CH₃, or —CF₃.

Embodiment 9: The compound of any one of embodiments 1 to 6, wherein R⁵is H, F, Cl, —CN, C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B),or —C(O)N(R⁸)SO₂R⁹.

Embodiment 10: The compound of embodiment 9, wherein R⁵ is C₁₋₆ alkylsubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹.

Embodiment 11: The compound of embodiment 10, wherein R⁴ is H, F, Cl,—CN, —CH₃, or —CF₃.

Embodiment 12: The compound of embodiment 10 or 11, wherein R⁴ is H, andR⁵ is —(C₁₋₆ alkylene)-N(R^(f))C(O)R^(a); C₁₋₆ alkyl substituted with 1,2, 3, 4 or 5 substituents independently selected from R¹⁰, —NH—SO₂R⁹,—NH—R^(8B), or —C(O)NH—SO₂R⁹.

Embodiment 13: The compound of embodiment 12, wherein R⁵ is—CH₂NHC(O)-(cyclopropyl), —NHCH₂CH(OH)CF₃, or—C(O)NHSO₂-(2-chlorophenyl).

Embodiment 14: The compound of embodiment 12, wherein R⁵ is —NHSO₂R⁹,and R⁹ is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, or C₆₋₁₀ aryl optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰.

Embodiment 15: The compound of embodiment 14, wherein R⁵ is—NHSO₂-(2-chlorophenyl), —NHSO₂—CH₂CH₂CH₃, or —NHSO₂—CH₂-(phenyl).

Embodiment 16: The compound of any one of embodiments 1 to 9, wherein R⁴is —NR⁸C(O)R⁷ or —NR⁸SO₂R⁹.

Embodiment 17: The compound of embodiment 16, wherein R⁴ is —NHC(O)R⁷,and R⁷ is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰, or C₃₋₈ cycloalkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰.

Embodiment 18: The compound of embodiment 16, wherein R⁴ is —NH—SO₂R⁹,and R⁹ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, or 5- to 14-memberedheteroaryl, wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl and 5-to 14-membered heteroaryl of R⁹ are independently optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰.

Embodiment 19: The compound of embodiment 18, wherein R⁹ is C₁₋₆ alkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰.

Embodiment 20: The compound of embodiment 18, wherein R⁹ is C₃₋₈cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰.

Embodiment 21: The compound of embodiment 18, wherein R⁹ is C₆₋₁₀ aryloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰.

Embodiment 22: The compound of embodiment 18, wherein R⁹ is 5- to14-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰.

Embodiment 23: The compound of embodiment 18, wherein R⁹ is selectedfrom the group consisting of cyclopentyl, cyclohexyl, phenyl,2-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-(difluoromethoxy)phenyl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,3,5-difluorophenyl, 3-pyridyl, 1-methyl-1H-imidazol-4-yl,1-methyl-1H-pyrazol-4-yl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 3-chlorobenzyl,4-chlorobenzyl, (1-methyl-1H-pyrazol-3-yl)methyl,(5-methylisoxazol-3-yl)methyl, (pyridin-2-yl)methyl,(pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl,cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl,(3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl,(spiro[3,3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, n-propyl, 3-cyano-2,2-dimethylpropyl,3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl,3,3-dimethylbutyl, 3-cyano-3-methylbutyl and 4,4-dimethylpentyl.

Embodiment 24: The compound of embodiment 16, wherein R⁷ is selectedfrom the group consisting of cyclopropyl, spiro[2,2]pentyl,cyclohexylmethyl and 4-chlorobenzyl.

Embodiment 25: The compound of any one of embodiments 1 to 24, whereinR¹ is C₃₋₁₂ cycloalkyl; 3- to 14-membered heterocyclyl; —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), or —(C₁₋₆alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to 14-memberedheterocyclyl, and C₁₋₆ alkylene of R¹ are independently optimallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰.

Embodiment 26: The compound of embodiment 25, wherein R¹ is C₃₋₁₂cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰.

Embodiment 27: The compound of embodiment 25, wherein R¹ is 3- to14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰.

Embodiment 28: The compound of embodiment 25, wherein R¹ is cyclohexylor piperidinyl, each is independently optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from the group consistingof F, —CH₃, —OH, oxo, and —NH₂.

Embodiment 29: The compound of embodiment 28, wherein R¹ is selectedfrom the group consisting of piperidin-3-yl, 5-fluoropiperidin-3-yl,5-methylpiperidin-3-yl and 5-fluoro-5-methylpiperidin-3-yl.

Embodiment 30: The compound of embodiment 25, wherein R¹ is —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl) optimally substituted with 1,2, 3, 4 or 5 substituents independently selected from R¹⁰.

Embodiment 31: The compound of embodiment 25, wherein R¹ is —(C₁₋₆alkylene)-NR^(1a)R^(1b).

Embodiment 32: The compound of embodiment 31, wherein R^(1a) and R^(1b)are independently hydrogen or C₁₋₆ alkyl.

Embodiment 33: The compound of any me of embodiments 1 to 32, wherein R⁰is H.

Embodiment 34: The compound of embodiment 1, wherein the compound is ofthe Formula (Ia):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁵, R⁶ andR⁹ are as defined in embodiment 1.

Embodiment 35: The compound of embodiment 1, wherein the compound is ofthe Formula (Ib):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁵, R⁶ andR⁷ are as defined in embodiment 1.

Embodiment 36: The compound of embodiment 1, wherein the compound is ofthe Formula (Ic):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R^(2B), R³, R⁶ and R⁹are as defined in embodiment 1.

Embodiment 37: The compound of embodiment 1, wherein the compound is ofthe Formula (Id):

wherein R^(6A) is hydrogen or R⁶; R²¹ and R²² are independently H, F,—CH₃ or —NH₂, and R^(2A), R^(2B), R³, R⁴, R⁵ and R⁶ are as defined inembodiment 1.

Embodiment 38: The compound of embodiment 37, wherein the compound is ofthe Formula (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6) or (Id-7):

Embodiment 39: The compound of embodiment 1, wherein the compound is ofthe Formula (Ie):

wherein R^(6A) is hydrogen or R⁶; R²¹ and R²² are independently H, F,—CH₃ or —NH₂. and R^(2A), R^(2B), R³, R⁵, R⁶ and R⁹ are as defined inembodiment 1.

Embodiment 40: The compound of embodiment 39, wherein the compound is ofthe Formula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6) or (Ie-7):

Embodiment 41: The compound of any one of embodiments 34 to 40, whereinR^(6A) is H.

Embodiment 42: The compound of embodiment 1, wherein the compound isselected from Compound Nos. 101-247 in Table 1, or a pharmaceuticallyacceptable salt thereof; or the compound is selected from Compound Nos.101-238 in Table 1, or a pharmaceutically acceptable salt thereof; orthe compound is selected from Compound Nos. 101-389 in Table 1, or apharmaceutically acceptable salt thereof; or the compound is selectedfrom Compound Nos. 101-238 and 248-389 in Table 1, or a pharmaceuticallyacceptable salt thereof; or the compound is selected from Compound Nos.248-389 in Table 1, or a pharmaceutically acceptable salt thereof; orthe compound is selected from Compound Nos. 101-238, 248-380 and 382-389in Table 1, or a pharmaceutically acceptable salt thereof; or thecompound is selected from Compound Nos. 248-380 and 382-389 in Table 1,or a pharmaceutically acceptable salt thereof.

Embodiment 43: A pharmaceutical composition comprising a compound of anyof embodiments 1 to 42, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.

Embodiment 44: A method of treating an IRE1-related disease or disorder,the method comprising administering to the subject having anIRE1-related disease or disorder an effective amount of the compound ofany of embodiments 1 to 42 or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition of embodiment 43.

Embodiment 45: The method of embodiment 44, wherein the IRE1-relateddisease or disorder is cancer.

Embodiment 46: The method of embodiment 45, wherein the cancer issquamous cell carcinoma, small-cell lung cancer, non-small cell lungcancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer,peritoneum cancer, hepatocellular cancer, stomach cancer,gastrointestinal cancer, esophageal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial cancer, uterine cancer, salivary gland carcinoma, renalcancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellularcarcinoma (HCC), anal carcinoma, penile carcinoma, or head and neckcancer.

Embodiment 47: The method of embodiment 45, wherein the cancer islymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), myelodysplasticsyndrome (MDS), or myeloproliferative disease (MPD).

Embodiment 48: The method of embodiment 44, wherein the IRE1-relateddisease or disorder is multiple myeloma.

Embodiment 49: The method of embodiment 44, wherein the IRE1-relateddisease or disorder is a triple-negative breast cancer (TNBC).

Embodiment 50: The method of any one of embodiments 44 to 49, furthercomprising administering one or more additional therapeutic agent(s)selected from the group consisting of an anti-inflammatory agent, acorticosteroid, an immunomodulatory agent, anti-cancer agent, anapoptosis-enhancer, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, an agent for treating metabolic disorders, an agentfor treating autoimmune disorders, and an agent for treatingimmunodeficiency disorders.

Embodiment 51: The method of embodiment 50, wherein the additionaltherapeutic agent is a corticosteroid, a proteasome inhibitor, animmunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody,an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-interleukin-6antibody, or a combination thereof.

Embodiment 52: The method of embodiment 51, wherein the corticosteroidcomprises dexamethasone

Embodiment 53: The method of embodiment 51, wherein proteasome inhibitorcomprises carfilzomib, ixazomib or bortezomib.

Embodiment 54: The method of embodiment 51, wherein immunomodulatoryagent comprises lenalidomide or pomalidomide.

Embodiment 55: The method of embodiment 51, wherein the anti-PD-L1antibody comprises, avelumab, durvalumab, or atezolizumab.

Embodiment 56: The method of embodiment 51, wherein the anti-PD-1antibody comprises pembrolizumab or nivolumab.

Embodiment 57: The method of any one of embodiments 44 to 56, furthercomprising administering radiotherapy.

Embodiment 58: Use of a compound according to any of embodiments 1 to42, or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to embodiment 43, in the manufacture of amedicament for the treatment of an IRE1-related disease or disorder.

Embodiment 59: The use of embodiment 58, wherein the IRE1-relateddisease or disorder is cancer.

Embodiment 60: The method of embodiment 59, wherein the cancer issquamous cell carcinoma, small-cell lung cancer, non-small cell lungcancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer,peritoneum cancer, hepatocellular cancer, stomach cancer,gastrointestinal cancer, esophageal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial cancer, uterine cancer, salivary gland carcinoma, renalcancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellularcarcinoma (HCC), anal carcinoma, penile carcinoma, or head and neckcancer.

Embodiment 61: The method of embodiment 59, wherein the cancer islymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), myelodysplasticsyndrome (MDS), or myeloproliferative disease (MPD).

Embodiment 62: The method of embodiment 58, wherein the IRE1-relateddisease or disorder is multiple myeloma.

Embodiment 63: The method of embodiment 58, wherein the IRE1-relateddisease or disorder is a triple-negative breast cancer (TNBC).

Embodiment 64: A compound according to any of embodiments 1 to 42, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to embodiment 43, for use in a method for treatingan IRE1-related disease or disorder.

Embodiment 65: A method of inhibiting or killing a cancer cellexpressing Ire1, the method comprising contacting the cancer cellexpressing Ire1 with a compound or pharmaceutically acceptable saltthereof, of any one of embodiments 1 to 42 or a pharmaceuticalcomposition of embodiment 43.

Embodiment 66: The method of embodiment 65, wherein the inhibiting orkilling is performed in vivo

Embodiment 67: The method of embodiment 65, wherein the cancer cellexpressing Ire1 is in a human

Embodiment 68: A method of modulating Ire1 activity, the methodcomprising contacting Ire1 with a compound or pharmaceuticallyacceptable salt thereof of any me of embodiments 1 to 42 or apharmaceutical composition of embodiment 43.

Embodiment 69: A kit for treating a condition mediated by IRE1,comprising:

a) a pharmaceutical composition of claim 45; and

b) instructions for use.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES Synthetic Examples

Exemplary Formula I compounds in Table 1 were made, characterized, andtested for binding to IRE1α (alpha). Where more than (me name isassociated with a Formula I compound or intermediate, the chemicalstructure shall define the compound. Listed in Table A1 are the compoundnames (including the salt form where applicable), MS m/z for [M+H]³⁰, ¹HNMR data, and the Example # where the synthetic protocols or analoguoussynthetic protocols are described.

TABLE A1 Cpd MS ¹H NMR Synth. No. Name m/z (ppm) Method 101N-[4-[[3-[2-[(4- 565.1 (400 MHz, CD₃OD) δ 8.50 (dd, J = 7.6, Exampleaminocyclohexyl)amino]pyrimidin- 2.0 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H),1 4-yl]-2-pyridyl]oxy]- 8.12 (dd, J = 4.8, 2.0 Hz, 1H), 8.08-8.063-methyl-phenyl]-2-chloro- (m, 1H), 7.60-7.57 (m, 2H), 7.48-7.43benzenesulfonamide (m, 2H), 7.24-7.21 (m, 1H), 7.10-7.09 hydrochloride(m, 1H), 7.06-7.04 (m, 1H), 6.91-6.89 (m, 1H), 3.98-3.90 (m, 1H),3.17-3.14 (m, 1H), 2.25-2.22 (m, 2H), 2.11-2.03 (m, 2H), 2.03 (s, 3H),1.61-1.49 (m, 4H). 102 N-[4-[[3-[2-[(4- 583.2 (400 MHz, CD₃OD) δ 8.52(d, J = 7.6 Hz, Example aminocyclohexyl)amino]pyrimidin- 1H), 8.32 (d, J= 6.0 Hz, 1H), 8.13 (d, J = 2 4-yl]-2-pyridyl]oxy]- 7.6 Hz, 2H),7.61-7.57 (m, 2H), 7.51- 3-fluoro-5-methyl-phenyl]- 7.47 (m, 2H),7.28-7.25 (m, 1H), 6.94- 2-chloro- 6.89 (m, 2H), 4.13-3.84 (m, 1H),3.20- benzenesulfonamide 3.14 (m, 1H), 2.24 (d, J = 11.2 Hz, 2H),hydrochloride 2.14 (d, J = 12.0 Hz, 2H), 2.08 (s, 3H), 1.65-1.48 (m,4H). 103 (S)-N-((2- 579.2 (400 MHz, CD₃OD) δ 8.33 (d, J = 4.8 Hz,Example chlorophenyl)sulfonyl)-4- 1H), 8.28 (d, J = 6.4 Hz, 1H),8.17-8.13 3 methyl-3-((3-(2-(piperidin- (m, 2H), 7.80 (d, J = 7.6 Hz,1H), 7.67 (s, 3-ylamino)pyrimidin-4- 1H), 7.46-7.41 (m, 3H), 7.28 (d, J= 7.6 yl)pyridin-2- Hz, 1H), 7.21-7.19 (m, 2H), 4.27-4.23yl)oxy)benzamide (m, 1H), 3.63-3.61 (m, 1H), 3.36-3.35 (m, 1H),2.96-2.82 (m, 2H), 2.19 (s, 3H), 2.07-1.98 (m, 2H), 1.79-1.67 (m, 2H).104 N-[4-[[3-[2-[(4- 603 (400 MHz, CD₃OD) δ 8.51-8.50 (m, Exampleaminocyclohexyl)amino]pyrimidin- 1H), 8.34 (d, J = 6.0 Hz, 1H),8.18-8.13 4 4-yl]-2-pyridyl]oxy]- (m, 2H), 7.63 (d, J = 3.6 Hz, 2H),7.55- 3-chloro-5-fluoro-phenyl]-2- 7.48 (m, 2H), 7.30 (dd, J = 7.6, 4.8Hz, chloro-benzenesulfonamide 1H), 7.13 (s, 1H), 7.06 (dd, J = 11.2, 2.4hydrochloride Hz, 1H), 4.05-3.87 (m, 1H), 3.19-3.14 (m, 1H), 2.24 (d, J= 12.4 Hz, 2H), 2.13 (d, J = 12.4 Hz, 2H), 1.64-1.47 (m, 4H). 105(S)-3,3,3-trifluoro-N-(2- 541.1 (400 MHz, CD₃OD) δ .78 (br s, 1H), 8.47Example fluoro-4-((3-(2-(piperidin-3- (d, J = 6.6 Hz, 1H), 8.35 (dd, J =4.7, 1.9 5 ylamino)pyrimidin-4- Hz, 1H), 7.90 (br s, 1H), 7.57 (t, J =8.9 yl)pyridin-2- Hz, 1H), 7.35-7.44 (m, 1H), 7.21 (br d, J =yl)oxy)phenyl)propane-1- 11 Hz, 1H), 7.07 (br d, J = 8.8 Hz, 1H),sulfonamide hydrochloride 4.64 (br s, 1H), 3.64 (br dd, J = 11.9, 3.5Hz, 1H), 3.32-3.39 (m, 3H), 3.00-3.16 (m, 2H), 2.69-2.85 (m, 2H),2.19-2.29 (m, 1H), 2.07-2.18 (m, 1H), 1.78-2.03 (m, 2H). 106(S)-N-(2-fluoro-4-((3-(2- 535.2 (400 MHz, CD₃OD) δ 8.75 (br s, 1H),Example (piperidin-3- 8.47 (d, J = 6.8 Hz, 1H), 8.36 (dd, J = 4.9, 5ylamino)pyrimidin-4- 2.0 Hz, 1H), 7.89 (br d, J = 6.2 Hz, 1H),yl)pyridin-2-yl)oxy)phenyl)- 7.33-7.47 (m, 7H), 7.14 (dd, J = 11.1, 2.51-phenylmethanesulfonamide Hz, 1H), 6.93-7.01 (m, 1H), 4.63 (br s,hydrochloride 1H), 4.46 (s, 2H), 3.64 (dd, J = 12.3, 3.8 Hz, 1H),3.35-3.43 (m, 1H), 3.03-3.16 (m, 2H), 2.19-2.30 (m, 1H), 2.09-2.18 (m,1H), 1.80-2.02 (m, 2H). 107 (S)-N-(2,5-difluoro-4-((3-(2- 553.2 (400MHz, CD₃OD) δ 8.73 (br s, 1H), Example (piperidin-3- 8.48 (d, J = 6.4Hz, 1H), 8.33 (dd, J = 1.76, 5 ylamino)pyrimidin-4- 4.85 Hz, 1H), 7.85(d, J = 4.41 Hz, 1H), yl)pyridin-2-yl)oxy)phenyl)- 7.37-7.43 (m, 3H),7.31-7.36 (m, 3H), 1-phenylmethanesulfonamide 7.24 (ddd, J = 7.17,11.08, 16.37 Hz, 2H), hydrochloride 4.61 (br s, 1H), 4.51 (s, 2H), 3.65(dd, J = 3.64, 12.24 Hz, 1H), 3.35-3.42 (m, 1H), 3.02-3.15 (m, 2H),2.20-2.28 (m, 1H), 2.09-2.18 (m, 1H), 1.80-2.02 (m, 2H). 108(S)-N-(2,3-difluoro-4-((3-(2- 553.2 (400 MHz, CD₃OD) δ 8.72 (br s, 1H),Example (piperidin-3- 8.48 (dd, J = 6.5, 2.1 Hz, 1H), 8.33 (br d, 5ylamino)pyrimidin-4- J = 4.6 Hz, 1H), 7.85 (br s, 1H), 7.31-7.43yl)pyridin-2-yl)oxy)phenyl)- (m, 6H), 7.24 (dt, J = 2.4, 8.6 Hz, 1H),1-phenylmethanesulfonamide 7.00-7.11 (m, 1H), 4.57 (br s, 1H), 4.51hydrochloride (s, 2H), 3.65 (dd, J = 3.1, 12.1 Hz, 1H), 3.39 (br d, J =12.8 Hz, 1H), 3.02-3.15 (m, 2H), 2.24 (br d, J = 12.57 Hz, 1H), 2.08-2.19 (m, 1H), 1.79-2.01 (m, 2H). 109 (S)-N-(2,5-difluoro-4-((3-(2- 559.1(400 MHz, CD₃OD) δ 8.75 (br s, 1H), Example (piperidin-3- 8.48 (d, J =6.6 Hz, 1H), 8.33 (d, J = 5.1 Hz, 5 ylamino)pyrimidin-4- 1H), 7.90 (brd, J = 5.7 Hz, 1H), 7.48 (dd, yl)pyridin-2-yl)oxy)phenyl)- J = 7.39,11.14 Hz, 1H), 7.35-7.44 (m, 2H), 3,3,3-trifluoropropane-1- 4.63 (br s,1H), 3.65 (br dd, J = 3.64, 12.46 sulfonamide hydrochloride Hz, 1H),3.36-3.43 (m, 3H), 3.01-3.16 (m, 2H), 2.67-2.85 (m, 2H), 2.25 (br d, J =9.70 Hz, 1H), 2.07-2.18 (m, 1H), 1.80-2.02 (m, 2H). 110(S)-N-(2,5-difluoro-4-((3-(2- (400 MHz, DMSO-d₆) δ 8.80 (br s, 1H),Example (piperidin-3- 8.49 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 2.0, 5ylamino)pyrimidin-4- 4.9 Hz, 1H), 7.93 (br d, J = 6.4 Hz, 1H),yl)pyridin-2-yl)oxy)phenyl)- 7.45-7.37 (m, 2H), 7.24-7.17 (m, 1H),3,3,3-trifluoropropane-1- 4.67 (br s, 1H), 3.66 (br dd, J = 3.6, 12.2sulfonamide hydrochloride Hz, 1H), 3.45-3.36 (m, 3H), 3.15-3.03 (m, 2H),2.83-2.71 (m, 2H), 2.29-2.09 (m, 2H), 2.02-1.84 (m, 2H). 111N-(2,3-difluoro-4-((3-(2- 567.5 (400 MHz, DMSO-d₆) δ 9.98 (s, 1 H),9.40- Example (((3S,5R)-5-methylpiperidin- 9.28 (m, 2H), 8.69-8.45 (m,2H), 8.25 6 3-yl)amino)pyrimidin-4- (d, J = 2.8 Hz, 1 H), 7.67 (s, 1 H),7.40- yl)pyridin-2-yl)oxy)phenyl)- 7.35 (m, 7H), 7.25-7.21 (m, 2H), 4.561-phenylmethanesulfonamide (s, 2 H), 4.34 (s, 1 H), 3.44 (s, 1 H), 3.19-hydrochloride 3.17 (m, 1H), 2.61-2.58 (m, 1H), 2.44- 2.41 (m, 1H),2.06-2.02 (m, 2H), 1.31- 1.25 (m, 1H), 0.94 (d, J = 6.8 Hz, 1 H). 112N-(2,3-difluoro-4-((3-(2- 571.1 (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.78Example (((3S,5S)-5-fluoropiperidin- (s, 1H), 9.24 (s, 1H), 8.46-8.48(m, 1H), 6 3-yl)amino)pyrimidin-4- 8.25-8.27 (m, 1H), 7.68 (s, 1H),7.37- yl)pyridin-2-yl)oxy)phenyl)- 7.40 (m, 7H), 7.18-7.23 (m, 2H), 5.23(d, 1-phenylmethanesulfonamide J = 48.8 Hz, 1H), 4.56 (s, 2H), 4.49 (s,1H), 3.45-3.62 (m, 3H), 3.13-3.30 (m, 1H), 2.50-2.85 (m, 1H), 2.33 (s,1H), 1.86-2.01 (m, 1H). 113 (S)-1-phenyl-N-(4-((3-(2- 585.3 (400 MHz,DMSO-d₆) δ 8.41-8.32 (M, Example (piperidin-3- 2H), 8.22 (dd, J = 4.8,2.2 Hz), 7.46-7.12 5 ylamino)pyrimidin-4- (m, 10H), 7.06 (dd, J = 9.0,2.8 Hz), 4.16- yl)pyridin-2-yl)oxy)-2- 4.08 (br s, 1H), 3.97 (s, 2H),3.20-3.07 (trifluoromethyl)phenyl)methanesulfonamide (m, 1H), 2.83-2.70(m, 2H), 1.98-1.91 (m, 1H), 1.80-1.70 (m, 1H), 1.70-1.54 (m, 2H). 114(S)-2-chloro-N-(3-fluoro-5- 569.1 (400 MHz, DMSO-d₆) δ 10.91 (s, 1H),Example methyl-4-((3-(2-(piperidin- 9.01 (s, 1H), 8.63 (s, 1H), 8.41 (d,J = 4.8 7 3-ylamino)pyrimidin-4- Hz, 1H), 8.15-8.10 (m, 2H), 7.69-7.57yl)pyridin-2- (m, 3H), 7.38-7.25 (m, 2H), 6.90-6.85yl)oxy)phenyl)benzenesulfonamide (m, 2H), 4.35-4.20 (m, 1H), 3.41-3.37hydrochloride (m, 1H), 3.19-3.15 (m, 1H), 2.87-2.73 (m, 2H), 2.03 (s,3H), 2.00-1.85 (m, 2H), 1.80-1.58 (m, 2H). 115(S)-N-(3-fluoro-5-methyl-4- 515.1 (400 MHz, DMSO-d₆) δ 8.42 (s, 1H),8.37 Example ((3-(2-(piperidin-3- (d, J = 5.2 Hz, 1H), 8.16-8.15 (m,1H), 7 ylamino)pyrimidin-4- 7.31-7.28 (m, 1H), 7.24 (d, J = 4.8 Hz,yl)pyridin-2- 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.99-6.89yl)oxy)phenyl)butane-1- (m, 2H), 3.94-3.80 (m, 1H), 3.20-3.04sulfonamide hydrochloride (m, 4H), 2.83-2.76 (m, 1H), 2.47-2.37 (m, 2H),2.10 (s, 3H), 1.95-1.86 (m, 1H), 1.73-1.60 (m, 3H), 1.53-1.32 (m, 4H),0.86 (t, J = 7.2 Hz, 3H). 116 (S)-N-(3-fluoro-5-methyl-4- 527.1 (400MHz, DMSO-d₆) δ 10.00 (s, 1H), Example ((3-(2-(piperidin-3- 9.63-9.14(m, 2H), 8.89-8.65 (m, 1H), 7 ylamino)pyrimidin-4- 8.47 (d, J = 5.2 Hz,1H), 8.21 (d, J = 3.6 yl)pyridin-2- Hz, 1H), 8.11-7.70 (m, 1H),7.56-7.29 yl)oxy)phenyl)cyclopentanesulfonamide (m, 2H), 7.09-6.92 (m,2H), 4.50-4.20 hydrochloride (m, 1H), 3.71-3.58 (m, 1H), 3.49-3.33 (m,1H), 3.24-3.08 (m, 1H), 2.89-2.73 (m, 2H), 2.11 (s, 3H), 2.03-1.98 (m,1H), 1.96-1.85 (m, 5H), 1.83-1.73 (m, 1H), 1.69-1.42 (m, 5H). 117(S)-N-(3-fluoro-5-methyl-4- 541.1 (400 MHz, DMSO-d₆) δ 10.01 (s, 1H),Example ((3-(2-(piperidin-3- 9.66-9.23 (m, 2H), 8.86-8.67 (m, 1H), 7ylamino)pyrimidin-4- 8.47 (d, J = 5.2 Hz, 1H), 8.26-8.19 (m,yl)pyridin-2- 1H), 7.60-7.38 (m, 1H), 7.37-7.28 (m,yl)oxy)phenyl)cyclohexanesulfonamide 1H), 7.07-7.01 (m, 1H), 6.98 (s,1H), hydrochloride 4.55-4.18 (m, 1H), 3.44-3.35 (m, 1H), 3.22-3.14 (m,1H), 3.13-3.04 (m, 1H), 2.91-2.75 (m, 2H), 2.11 (s, 3H), 2.08- 1.96 (m,3H), 1.95-1.86 (m, 1H), 1.84- 1.72 (m, 3H), 1.70-1.54 (m, 2H), 1.51-1.34 (m, 2H), 1.33-1.19 (m, 2H), 1.18- 1.05 (m, 1H). 118N-(4-((3-(2-(((1r,4r)-4- 515.1 (400 MHz, DMSO-d₆) δ 10.07 (s, 1H),Example aminocyclohexyl)amino)pyrimidin- 8.46 (s, 2H), 8.31-8.14 (m,4H), 7.53- 2 4-yl)pyridin-2- 7.33 (m, 2H), 7.07-6.95 (m, 2H), 4.00-yl)oxy)-3-fluoro-5- 3.78 (m, 1H), 3.15 (t, J = 7.6 Hz, 2H),methylphenyl)propane-1- 3.06-2.95 (m, 1H), 2.13 (s, 3H), 2.10-1.99 (m,4H), sulfonamide hydrochloride 1.75-1.67 (m, 2H), 1.58- 1.37 (m, 4H),8.47 (t, J = 7.2 Hz, 3H). 119 N-(4-((3-(2-(((1r,4r)-4- 563.1 (400 MHz,DMSO-d₆) δ 10.08 (s, 1H), Example aminocyclohexyl)amino)pyrimidin- 8.46(m, 2H), 8.29-8.10 (m, 5H), 7.46- 2 4-yl)pyridin-2- 7.42 (m, 1H),7.39-7.31 (m, 6H), 6.97- yl)oxy)-3-fluoro-5- 6.89 (m, 2H), 4.57 (s, 2H),3.92-3.79 methylphenyl)-1- (m, 1H), 3.07-2.94 (m, 1H), 2.12 (s,phenylmethanesulfonamide 3H), 2.09-1.99 (m, 4H), 1.55-1.36 (m,hydrochloride 4H). 120 N-(4-((3-(2-(((1r,4r)-4- 477.2 (400 MHz, DMSO-d₆)δ 10.56 (s, 1H), Example aminocyclohexyl)amino)pyrimidin- 8.44 (s, 2H),8.25-8.21 (m, 1H), 8.16- 2 4-yl)pyridin-2- 8.09 (m., 3H), 7.61-7.55 (m,1H), 7.44- yl)oxy)-3-fluoro-5- 7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.29methylphenyl)cyclopropanecarboxamide (s, 1H), 3.06-2.95 (m, 1H), 2.11(s, 3H), hydrochloride 2.08-1.98 (m, 4H), 1.87-1.79 (m, 1H), 1.58-1.32(m, 5H), 0.84-0.78 (m, 4H). 121 N-(4-((3-(2-(((1r,4r)-4- 535.0 (400 MHz,DMSO-d₆) δ 10.40 (s, 1H), Example aminocyclohexyl)amino)pyrimidin- 8.45(s, 2H), 8.27-8.22 (m, 1H), 8.15- 9 4-yl)pyridin-2- 8.05 (m, 2H),7.45-7.35 (m, 2H), 7.26- yl)oxy)-3-chloro-5- 7.15 (m, 2H), 3.90-3.80 (m,1H), 3.23 (t, fluorophenyl)propane-1- J = 7.6 Hz, 2H), 3.05-2.95(m, 1H),2.15- sulfonamide hydrochloride 1.95 (m, 4H), 1.77-1.67 (m, 2H), 1.55-1.33 (m, 4H), 0.97 (t, J = 7.2 Hz, 3H). 122 N-(4-((3-(2-(((1r,4r)-4-519.1 (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), Exampleaminocyclohexyl)amino)pyrimidin- 8.45-8.38 (m, 2H), 8.25-8.23 (m, 1H), 84-yl)pyridin-2- 8.00-7.90 (m, 2H), 7.60-7.50 (m, 1H), yl)oxy)-3,5-7.40-7.35 (m, 1H), 7.22-7.18 (m, 1H), difluorophenyl)propane-1- 7.04 (d,J = 9.2 Hz, 2H), 3.80-3.70 (m, sulfonamide hydrochloride 1H), 3.23 (t, J= 7.6 Hz, 2H), 3.05-2.95 (m, 1H), 2.07-2.95 (m, 4H), 1.73-1.64 (m, 2H),1.50-1.30 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H). 123 (S)-2-Chloro-N-(2,3-565.1 (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 8.37- Exampledimethyl-4-((3-(2-(piperidin- 8.32 (m, 1H), 8.12 (dd, J = 4.8, 2.0 Hz,10 3-ylamino)pyrimidin-4- 1H), 7.84 (dd, J = 7.8, 1.7 Hz, 1H), 7.65-yl)pyridin-2- 7.59 (m, 1H), 7.59-7.52 (m, 1H), 7.45-yl)oxy)phenyl)benzenesulfonamide 7.39 (m, 1H), 7.27-7.18 (m, 2H), 7.10(d, J = 7.9 Hz, 1H), 6.79-6.67 (m, 2H), 3.88 (s, 1H), 3.10 (d, J = 12.0Hz, 1H), 2.83 (d, J = 13.0 Hz, 1H), 2.48-2.42 (m, 2H), 2.13 (s, 3H),1.92 (s, 3H), 1.90 (d, J = 4.1 Hz, 2H), 1.70-1.63 (m, 1H), 1.52- 1.42(m, 2H). 124 (S)-N-(2,5-Dimethyl-4-((3- 497.2 (400 MHz, DMSO-d₆) δ 8.41(s, 2H), 8.35 Example (2-(piperidin-3- (d, J = 5.1 Hz, 1H), 8.17 (dd, J= 4.8, 2.0 10 ylamino)pyrimidin-4- Hz, 1H), 7.30-7.24 (m, 2H), 7.16 (s,yl)pyridin-2- 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.98 (s,yl)oxy)phenyl)propane-1- 1H), 3.84 (s, 1H), 3.12-3.02 (m, 2H),sulfonamide 2.79 (d, J = 12.3 Hz, 1H), 2.47-2.37 (m, 4H), 2.25 (s, 3H),2.02 (s, 3H), 1.90 (t, J = 5.6 Hz, 1H), 1.82-1.72 (m, 2H), 1.67- 1.60(m, 1H), 1.44 (q, J = 13.4, 12.5 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H). 125(S)-2-chloro-N-(2,5- 565.2 (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.34Example dimethyl-4-((3-(2-(piperidin- (d, J = 5.1 Hz, 1H), 8.14 (dd, J =4.8, 2.0 10 3-ylamino)pyrimidin-4- Hz, 1H), 7.87 (dd, J = 7.9, 1.7 Hz,1H), yl)pyridin-2- 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.58 (td, J =yl)oxy)phenyl)benzenesulfonamide 7.6, 1.7 Hz, 1H), 7.44 (td, J = 7.6,1.4 Hz, 1H), 7.28-7.19 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.84 (d, J =11.5 Hz, 2H), 3.89 (s, 1H), 3.12 (d, J = 12.2 Hz, 1H), 2.85 (d, J = 12.1Hz, 1H), 2.48-2.41 (m, 2H), 2.05 (s, 3H), 1.94-1.88 (m, 2H), 1.87 (s,3H), 1.67 (d, J = 6.7 Hz, 1H), 1.48 (t, J = 8.9 Hz, 2H). 126(S)-N-(2,5-Dimethyl-4-((3- 497.2 (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 8.35Example (2-(piperidin-3- (d, J = 5.1 Hz, 1H), 8.17 (dd, J = 4.8, 2.0 10ylamino)pyrimidin-4- Hz, 1H), 7.30-7.24 (m, 2H), 7.16 (s, yl)pyridin-2-1H), 7.07 (d, J = 8.0 Hz, 1H), 6.98 (s, yl)oxy)phenyl)propane-1- 1H),3.84 (s, 1H), 3.12-3.02 (m, 2H), sulfonamide 2.79 (d, J = 12.3 Hz, 1H),2.47-2.37 (m, 4H), 2.25 (s, 3H), 2.02 (s, 3H), 1.90 (t, J = 5.6 Hz, 1H),1.82-1.72 (m, 2H), 1.67- 1.60 (m, 1H), 1.44 (q, J = 13.4, 12.5 Hz, 2H),1.01 (t, J = 7.5 Hz, 3H). 127 (S)-N-(4-fluoro-3-((3-(2- 487.2 (400 MHz,DMSO-d₆) δ 8.41 (s, 1H), 8.38 Example (piperidin-3- (d, J = 5.1 Hz, 1H),8.20 (dd, J = 4.8, 1.9 10 ylamino)pyrimidin-4- Hz, 1H), 7.37-7.29 (m,2H), 7.19 (d, J = yl)pyridin-2- 5.1 Hz, 1H), 7.15-7.06 (m, 3H), 3.86 (d,yl)oxy)phenyl)propane-1- J = 10.5 Hz, 1H), 3.13-3.03 (m, 3H),sulfonamide 2.80 (d, J = 12.4 Hz, 1H), 2.42 (dd, J = 11.7, 8.8 Hz, 1H),2.07 (s, 2H), 1.90 (d, J = 3.4 Hz, 1H), 1.73-1.60 (m, 2H), 1.45 (q, J =13.0, 12.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 128(S)-2-Chloro-N-(4-fluoro-3- 555.1 (400 MHz, DMSO-d₆) δ 8.38 (d, J = 5.1Example ((3-(2-(piperidin-3- Hz, 1H), 8.36 (s, 1H), 8.16 (dd, J = 4.8,10 ylamino)pyrimidin-4- 1.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.55-yl)pyridin-2- 7.46 (m, 2H), 7.40 (ddd, J = 7.8, 6.8, 1.9yl)oxy)phenyl)benzenesulfonamide Hz, 1H), 7.30 (dd, J = 7.5, 4.8 Hz,1H), 7.26 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.06 (dd, J =10.4, 8.9 Hz, 1H), 6.85 (dd, J = 7.1, 2.7 Hz, 1H), 6.80 (ddd, J = 8.8,4.0, 2.7 Hz, 1H), 3.97 (s, 1H), 3.24 (s, 1H), 3.00 (d, J = 12.3 Hz, 1H),2.68-2.52 (m, 2H), 1.98-1.87 (m, 1H), 1.75 (d, J = 5.9 Hz, 1H), 1.53 (t,J = 9.2 Hz, 2H). 129 (S)-2-Cyclohexyl-N-(2,3- 515.1 (400 MHz, DMSO-d₆) δ9.34 (s, 1H), 8.41 Example dimethyl-4-((3-(2-(piperidin- (s, 2H), 8.37(d, J = 5.1 Hz, 1H), 8.16 (dd, 11 3-ylamino)pyrimidin-4- J = 4.8, 2.0Hz, 1H), 7.31-7.22 (m, 2H), yl)pyridin-2- 7.09 (t, J = 8.8 Hz, 2H), 6.89(d, J = 8.5 yl)oxy)phenyl)acetamide Hz, 1H), 3.87 (s, 1H), 3.08 (d, J =11.8 Hz, 1H), 2.80 (d, J = 12.4 Hz, 1H), 2.47- 2.37 (m, 3H), 2.21 (d, J= 6.8 Hz, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 1.91 (s, 1H), 1.71 (dd, J =32.3, 14.1 Hz, 5H), 1.46 (q, J = 13.5, 12.7 Hz, 2H), 1.22 (dq, J = 24.6,11.8, 11.3 Hz, 3H), 1.02 (q, J = 11.4, 11.0 Hz, 2H). 130(S)-2-(4-Chlorophenyl)-N- 543.2 (400 MHz, DMSO-d₆) δ 9.65 (s, 1H), 8.41Example (2,3-dimethyl-4-((3-(2- (s, 1H), 8.36 (d, J = 5.1 Hz, 1H), 8.15(dd, 11 (piperidin-3- J = 4.8, 2.0 Hz, 1H), 7.41 (s, 4H), 7.30-ylamino)pyrimidin-4- 7.22 (m, 2H), 7.12 (d, J = 8.6 Hz, 1H),yl)pyridin-2- 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.5yl)oxy)phenyl)acetamide Hz, 1H), 3.84 (s, 1H), 3.68 (s, 2H), 3.07 (d, J= 11.7 Hz, 1H), 2.78 (d, J = 12.4 Hz, 1H), 2.46-2.37 (m, 3H), 2.07 (s,3H), 2.00 (s, 3H), 1.91 (d, J = 11.1 Hz, 1H), 1.67-1.58 (m, 1H), 1.46(dt, J = 26.4, 14.0 Hz, 2H). 131 (S)-2-chloro-N-(3,5- 565.2 (500 MHz,d₆-DMSO) δ 10.53 (s, 1H), Example dimethyl-4-((3-(2-(piperidin-9.11-8.70 (br s, 1H), 8.87 (s, 1H), 8.68- 12 3-ylamino)pyrimidin-4- 8.20(br s, 1H), 8.41 (d, J = 5.2 Hz, 1H), yl)pyridin-2- 8.12 (dd, J = 4.8,1.8 Hz, 1H), 8.08 (d, J = yl)oxy)phenyl)benzenesulfonamide 7.2 Hz, 1H),7.72-7.61 (m, 2H), 7.61- hydrochloride 7.51 (m, 1H), 7.47 (d, J = 7.4Hz, 1H), 7.41 (s, 1H), 7.24 (dd, J = 7.5, 4.8 Hz, 1H), 6.87 (s, 2H),4.30-4.15 (m, 1H), 3.77- 3.65 (m, 1H), 3.19 (d, J = 12.3 Hz, 1H),2.92-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.94-1.90 (m, 7H), 1.73 (q, J =13.3 Hz, 1H), 1.61 (q, J = 10.4 Hz, 1H). 132 (S)-2-chloro-N-(3-((3-(2-537.1 (400 MHz, d₆-DMSO) δ 10.82 (s, 1H), Example (piperidin-3-9.15-8.89 (m, 2H), 8.57 (s, 1H), 8.40 (d, 13 ylamino)pyrimidin-4- J =5.2 Hz, 1H), 8.19 (dd, J = 4.8, 2.0 Hz, yl)pyridin-2- 1H), 8.03-7.99 (m,1H), 7.65 (dd, J = yl)oxy)phenyl)benzenesulfonamide 4.9, 1.2 Hz, 2H),7.60-7.48 (m, 2H), hydrochloride 7.33 (dd, J = 7.6, 4.8 Hz, 1H),7.28-7.18 (m, 2H), 6.93 (ddd, J = 8.2, 2.1, 0.8 Hz, 1H), 6.84 (t, J =2.1 Hz, 1H), 6.79 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H), 4.22 (s, 1H), 3.39(d, J = 10.7 Hz, 1H), 3.18 (d, J = 13.0 Hz, 1H), 2.92-2.72 (m, 2H),2.02-1.84 (m, 2H), 1.79-1.54 (m, 2H). 133 (S)-1-phenyl-N-(3-((3-(2-517.2 (400 MHz, d₆-DMSO) δ 10.01 (s, 1H), Example (piperidin-3-9.20-8.85 (m, 2H), 8.58 (s, 1H), 8.45 (d, 14 ylamino)pyrimidin-4- J =5.2 Hz, 1H), 8.27 (dd, J = 4.8, 2.0 Hz, yl)pyridin-2- 1H), 7.60 (d, J =6.9 Hz, 1H), 7.40-7.30 yl)oxy)phenyl)methanesulfonamide (m, 6H),7.29-7.23 (m, 2H), 7.05 (dd, J = hydrochloride 8.2, 1.3 Hz, 1H),6.93-6.85 (m, 2H), 4.49 (s, 2H), 4.24 (s, 1H), 3.40 (d, J = 12.4 Hz,1H), 3.19 (d, J = 11.9 Hz, 1H), 2.92-2.73 (m, 2H), 1.95 (ddd, J = 18.4,13.7, 4.1 Hz, 2H), 1.82-1.53 (m, 2H). 134 (S)-2-chloro-N-(4-((3-(2-537.0 (400 MHz, d₆-DMSO) δ 10.64 (s, 1H), Example (piperidin-3- 8.71(br.s, 2H), 8.57-8.42 (m, 1H), 8.38 15 ylamino)pyrimidin-4- (d, J = 5.2Hz, 1H), 8.17 (dd, J = 4.8, 1.9 yl)pyridin-2- Hz, 1H), 8.04 (d, J = 8.5Hz, 1H), 7.71- yl)oxy)phenyl)benzenesulfonamide 7.61 (m, 2H), 7.53 (ddd,J = 8.4, 6.7, 2.1 hydrochloride Hz, 1H), 7.46 (d, J = 6.9 Hz, 1H), 7.27(dd, J = 7.5, 4.9 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 8.9Hz, 2H), 4.26- 4.10 (m, 1H), 3.40 (d, J = 12.5 Hz, 1H), 3.18 (d, J =12.5 Hz, 1H), 2.92-2.70 (m, 2H), 2.01-1.82 (m, 2H), 1.76-1.51 (m, 2H).135 (S)-2-chloro-N-(4-methyl-3- 551.0 (400 MHz, d₆-DMSO) δ 10.65 (s,1H), Example ((3-(2-(piperidin-3- 9.16-8.82 (m, 2H), 8.61 (s, 1H), 8.41(d, 16 ylamino)pyrimidin-4- J = 5.2 Hz, 1H), 8.13 (dd, J = 4.8, 2.0 Hz,yl)pyridin-2- 1H), 7.99-7.94 (m, 1H), 7.64 (dd, J =yl)oxy)phenyl)benzenesulfonamide 4.9, 1.2 Hz, 2H), 7.60-7.52 (m, 1H),hydrochloride 7.53-7.44 (m, 1H), 7.29 (dd, J = 7.6, 4.8 Hz, 2H), 7.14(d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.2, 2.2 Hz, 1H), 6.78 (d, J = 2.2Hz, 1H), 4.25 (s, 1H), 3.43-3.35 (m, 1H), 3.24-3.11 (m, 1H), 2.93-2.72(m, 2H), 2.04-1.85 (m, 5H), 1.84-1.52 (m, 2H). 136(S)-N-(4-methyl-3-((3-(2- 531.1 (400 MHz, d₆-DMSO) δ 9.87 (s, 1H), 9.23-Example (piperidin-3- 8.88 (m, 2H), 8.46 (d, J = 5.3 Hz, 1H), 17ylamino)pyrimidin-4- 8.23 (dd, J = 4.8, 2.0 Hz, 1H), 7.60 (s,yl)pyridin-2-yl)oxy)phenyl)- 1H), 7.42 (s, 1H), 7.36-7.29 (m, 4H),1-phenylmethanesulfonamide 7.28-7.21 (m, 3H), 7.01 (dd, J = 8.2, 2.2hydrochloride Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 4.44 (s, 2H), 4.27 (s,1H), 3.47-3.32 (m, 2H), 3.25-3.12 (m, 1H), 2.92-2.74 (m, 2H), 2.06-1.95(m, 4H), 1.95-1.85 (m, 1H), 1.85-1.52 (m, 2H). 137(S)-2-chloro-N-(4-chloro-2- 589.0 (400 MHz, d₆-DMSO) δ 10.74 (s, 1H),Example fluoro-3-((3-(2-(piperidin-3- 9.00-8.73 (m, 2H), 8.58 (s, 1H),8.45 (d, 19 ylamino)pyrimidin-4- J = 5.1 Hz, 1H), 8.14 (dd, J = 4.8, 1.9Hz, yl)pyridin-2- 1H), 7.96-7.91 (m, 1H), 7.71-7.63 (m,yl)oxy)phenyl)benzenesulfonamide 2H), 7.58-7.49 (m, 2H), 7.40 (dd, J =hydrochloride 9.0, 1.9 Hz, 1H), 7.36 (dd, J = 7.6, 4.8 Hz, 1H), 7.29 (d,J = 3.9 Hz, 1H), 7.19 (dd, J = 8.9, 7.9 Hz, 1H), 4.23 (s, 1H), 3.40 (d,J = 11.1 Hz, 1H), 3.19 (d, J = 12.5 Hz, 1H), 2.82 (td, J = 20.8, 10.6Hz, 2H), 2.03- 1.85 (m, 2H), 1.66 (dq, J = 33.4, 10.8 Hz, 2H). 138(S)-N-(4-chloro-2-fluoro-3- 569.0 (400 MHz, d₆-DMSO) δ δ 8.54-8.39 (m,Example ((3-(2-(piperidin-3- 2H), 8.27-8.18 (m, 2H), 7.43-7.20 (m, 20ylamino)pyrimidin-4- 10H), 7.09 (dd, J = 9.1, 1.6 Hz, 1H), 4.16-4.05yl)pyridin-2-yl)oxy)phenyl)- (m, 3H), 3.06 (d, J = 12.3 Hz, 1H),1-phenylmethanesulfonamide 2.76-2.59 (m, 3H), 2.01-1.90 (m, 1H),1.88-1.76 (m, 1H), 1.68-1.51 (m, 2H). 139 (S)-2-chloro-N-(2-methyl-3-551.2 (400 MHz, d₆-DMSO) δ 10.00 (s, 1H), Example ((3-(2-(piperidin-3-8.84 (br s, 2H), 8.71-8.21 (br s, 1H), 21 ylamino)pyrimidin-4- 8.40 (d,J = 5.2 Hz, 1H), 8.13 (dd, J = 4.8, yl)pyridin-2- 1.9 Hz, 1H), 7.85 (dd,J = 7.9, 1.6 Hz, yl)oxy)phenyl)benzenesulfonamide 1H), 7.70 (dd, J =8.0, 1.3 Hz, 1H), 7.64 hydrochloride (td, J = 7.7, 1.6 Hz, 1H), 7.49(td, J = 7.7, 1.4 Hz, 2H), 7.33 (s, 1H), 7.25 (dd, J = 7.6, 4.8 Hz, 1H),7.10 (t, J = 8.1 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz,1H), 4.21 (s, 1H), 3.17 (d, J = 12.6 Hz, 1H), 2.89-2.70 (m, 2H), 1.95(m, 4H), 1.88 (dd, J = 10.6, 4.4 Hz, 1H), 1.78- 1.65 (m, 1H), 1.58 (q, J= 10.4 Hz, 1H). 140 (S)-N-(2-methyl-3-((3-(2- 531.2 (400 MHz, d₆-DMSO) δ9.28 (s, 1H), 8.88 Example (piperidin-3- (s, 1H), 9.22-8.73 (m, 1H),8.44 (d, J = 22 ylamino)pyrimidin-4- 5.2 Hz, 1H), 8.72-8.25 (m, 1H),8.19 yl)pyridin-2-yl)oxy)phenyl)- (dd, J = 4.8, 1.9 Hz, 1H), 7.52 (d, J= 7.3 1-phenylmethanesulfonamide Hz, 1H), 7.44-7.33 (m, 6H), 7.29 (dd, J= hydrochloride 7.6, 4.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.19 (dd, J = 8.0,1.3 Hz, 1H), 7.01 (dd, J = 7.7, 1.2 Hz, 1H), 4.49 (d, J = 8.7 Hz, 2H),4.24 (s, 1H), 3.19 (d, J = 16.1 Hz, 1H), 2.94-2.74 (m, 2H), 2.00 (s,4H), 1.91 (d, J = 14.5 Hz, 1H), 1.73 (q, J = 11.6 Hz, 1H), 1.61 (q, J =9.9 Hz, 1H). 141 (S)-2-chloro-N-(2-fluoro-3- 555.0 (400 MHz, d₆-DMSO) δ10.56 (s, 1H), Example ((3-(2-(piperidin-3- 8.84-8.63 (m, 2H), 8.59-8.45(m, 1H), 23 ylamino)pyrimidin-4- 8.42 (d, J = 5.1 Hz, 1H), 8.14 (dd, J =4.8, yl)pyridin-2- 1.9 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H),yl)oxy)phenyl)benzenesulfonamide 7.72-7.62 (m, 2H), 7.51 (ddd, J = 8.4,hydrochloride 6.5, 2.2 Hz, 2H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 7.25 (d,J = 4.1 Hz, 1H), 7.23- 7.08 (m, 3H), 4.29-4.08 (m, 1H), 3.20 (d, J =11.6 Hz, 2H), 2.95-2.72 (m, 2H), 2.05-1.83 (m, 2H), 1.79-1.49 (m, 2H).142 (S)-N-(2-fluoro-3-((3-(2- 535.0 (400 MHz, d₆-DMSO) δ 9.83 (s, 1H),8.85- Example (piperidin-3- 8.61 (m, 2H), 8.61-8.49 (m, 1H), 8.46 24ylamino)pyrimidin-4- (d, J = 5.2 Hz, 1H), 8.23 (dd, J = 4.8, 1.8yl)pyridin-2-yl)oxy)phenyl)- Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H),7.43-7.29 (m, 7H), 1-phenylmethanesulfonamide 7.28-7.12 (m, 3H), 4.51hydrochloride (s, 2H), 4.41-4.00 (m, 1H), 3.20 (d, J = 12.4 Hz, 2H),2.83 (td, J = 21.5, 11.3 Hz, 2H), 1.95 (ddd, J = 17.6, 12.5, 4.4 Hz,2H), 1.81-1.51 (m, 2H). 143 (S)-N-(4-chloro-2-fluoro-3- 521.0 (400 MHz,d₆-DMSO) δ 9.95 (s, 1H), Example ((3-(2-(piperidin-3- 9.02-8.74 (m, 2H),8.73-8.29 (m, 1H), 8.47 25 ylamino)pyrimidin-4- (d, J = 5.2 Hz, 1H),8.21 (dd, J = 4.8, 1.9 yl)pyridin-2- Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H),7.46 yl)oxy)phenyl)propane-1- (dd, J = 9.0, 1.7 Hz, 1H), 7.43-7.31 (m,sulfonamide hydrochloride 3H), 4.24 (s, 1H), 3.42 (d, J = 12.7 Hz, 1H),3.19 (d, J = 12.1 Hz, 1H), 3.16- 3.09 (m, 2H), 2.93-2.72 (m, 2H), 2.00(dd, J = 12.4, 4.1 Hz, 1H), 1.95-1.85 (m, 1H), 1.72 (p, J = 7.4 Hz, 3H),1.61 (q, J = 10.9 Hz, 1H), 0.95 (t, J = 7.4 Hz, 3H). 144(S)-N-(2-fluoro-3-((3-(2- 487.1 (400 MHz, d₆-DMSO) δ 9.79 (s, 1H),Example (piperidin-3- 9.04-8.77 (m, 2H), 8.73-8.48 (m, 1H), 8.45 26ylamino)pyrimidin-4- (d, J = 5.2 Hz, 1H), 8.21 (dd, J = 4.8, 1.9yl)pyridin-2- Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.41-7.28 (m, 3H),yl)oxy)phenyl)propane-1- 7.29-7.18 (m, 2H), 4.33-4.14 (m, 1H), 3.41 (d,J = 11.3 Hz, 1H), sulfonamidehydrochloride 3.19 (d, J = 13.4 Hz, 1H),3.14-3.04 (m, 2H), 2.93-2.73 (m, 2H), 2.07-1.84 (m, 2H), 1.80-1.67 (m,3H), 1.67-1.54 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H). 145(S)-1-cyclohexyl-N-(2,3- 559.2 (300 MHz, DMSO-d₆) δ 9.97 (s, 1H),Example difluoro-4-((3-(2-(piperidin- 9.25-9.50 (brs, 2H), 8.80-8.60(brs, 1H), 27 3-ylamino)pyrimidin-4- 8.48 (d, J = 5.4 Hz, 1H), 8.26 (dd,J = 4.8, yl)pyridin-2- 1.6 Hz, 1H), 8.00-7.85 (brs, 1H), 7.40-yl)oxy)phenyl)methanesulfonamide 7.25 (m, 4H), 4.35 (s, 1H), 3.40 (d, J= hydrochloride 7.0 Hz, 1H), 3.18 (d, J = 12.3 Hz, 1H), 3.09 (d, J = 5.7Hz, 2H), 2.89-2.76 (m, 2H), 2.05-1.83 (m, 6H), 1.61 (d, J = 13.8 Hz,4H), 1.34-1.00 (m, 5H). 146 (S)-N-(2,3-difluoro-4-((3-(2- 571.1 (400MHz, CD₃OD) δ 8.71 (s, 1H), 8.49 Example (piperidin-3- (d, J = 6.2 Hz,1H), 8.33 (s, 1H), 7.80 (s, 27 ylamino)pyrimidin-4- 1H), 7.57-7.47 (m,1H), 7.46-7.36 (m, yl)pyridin-2-yl)oxy)phenyl)- 2H), 7.34-7.26 (m, 1H),7.26-7.00 (m, 1-(2-fluorophenyl)methanesulfonamide 3H), 4.61 (s, 3H),3.72-3.58 (m, 1H), hydrochloride 3.40 (d, J = 12.9 Hz, 1H), 3.19-3.03(m, 2H), 2.24 (s, 1H), 2.18-2.10 (m, 1H), 1.95-1.85 (m, 2H). 147(S)-N-(2,3-difluoro-4-(3-(2- 467.2 (400 MHz, CD₃OD) δ 8.77 (d, J = 8.0Hz, Example (piperidin-3- 1H), 8.50 (d, J = 6.6 Hz, 1H), 8.33 (dd, J =28 ylamino)pyrimidin-4- 4.8, 1.9 Hz, 1H), 7.91 (d, J = 5.5 Hz,yl)pyridin-2- 1H), 7.80-7.66 (m, 1H), 7.41 (dd, J =yloxy)phenyl)cyclopropanecarboxamide 2.2, 4.8 Hz, 1H), 7.43-7.39 (m,1H), hydrochloride 4.63 (s, 1H), 3.67 (dd, J = 12.2, 3.9 Hz, 1H),3.43-3.38 (m, 1H), 3.19-3.01 (m, 2H), 2.32-2.21 (m, 1H), 2.18-2.12 (m,1H), 2.07-1.81 (m, 3H), 1.02-0.90 (m, 4H). 148(S)-N-(2,3-Difluoro-4-((3-(2- 555.1 (400 MHz, CD₃OD) δ 8.63 (s, 1H),8.49- Example (piperidin-3- 8.43 (m, 1H), 8.26 (s, 1H), 7.67 (s, 1H), 27ylamino)pyrimidin-4- 7.46-7.31 (m, 2H), 7.16 (t, J = 8.4 Hz,yl)pyridin-2-yl)oxy)phenyl)- 1H), 4.45 (s, 1H), 3.87 (t, J = 13.3 Hz,2,2-difluorobutane-1- 2H), 3.65 (d, J = 13.8 Hz, 1H), 3.38 (d, J =sulfonamide hydrochloride 12.9 Hz, 1H), 3.07 (t, J = 11.4 Hz, 2H),2.22-2.12 (m, 4H), 1.95-1.77 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H) 149(S)-N-(2,3-difluoro-4-((3-(2- 555.1 (300 MHz, CD₃OD) δ 8.83-8.80 (m,Example (piperidin-3- 1H), 8.522 (d, J = 6.6 Hz, 1H), 8.37- 27ylamino)pyrimidin-4- 3.35 (m, 1H), 7.96 (d, J = 6.6 Hz, 1H),yl)pyridin-2-yl)oxy)phenyl)- 7.50-7.36 (m, 2H), 7.34-7.16 (m, 1H),3,3-difluorobutane-1- 4.69 (s, 1H), 3.69 (d, J = 12.0 Hz, 1H),sulfonamide hydrochloride 3.48-3.35 (m, 3H), 3.24-3.02 (m, 2H),2.59-2.37 (m, 2H), 2.28 (d, J = 12.4 Hz, 1H), 2.16-2.14 (m, 1H),2.10-1.86 (m, 2H), 1.70 (t, J = 18.0 Hz, 3H). 150N-(2,3-difluoro-4-((3-(2- 493.2 (400 MHz, CD₃OD) δ 8.78 (d, J = 7.6 Hz,Example (((S)-piperidin-3- 1H), 8.50 (d, J = 6.8 Hz, 1H), 8.33 (d, J =29 yl)amino)pyrimidin-4- 4.8 Hz, 1H), 7.92 (d, J = 6.6 Hz, 1H), 7.73yl)pyridin-2- (d, J = 8.5 Hz, 1H), 7.41 (d, J = 4.8 Hz,yl)oxy)phenyl)spiro[2.2]pentane- 1H), 7.18-7.08 (m, 1H), 4.65 (s, 1H),1-carboxamide 3.71-3.63 (m, 1H), 3.53-3.38 (m, 1H), hydrochloride 3.08(dd, J = 13.4, 4.2 Hz, 2H), 2.28 (dd, J = 7.2, 4.8 Hz, 2H), 2.27-2.09(m, 1H), 2.05-1.83 (m, 2H), 1.65-1.49 (m, 1H), 1.48-1.39 (m, 1H),1.06-0.87 (m, 4H). 151 N-(2,3-difluoro-4-((3-(2- 493.2 (400 MHz, CD₃OD)δ 8.77 (s, 1H), 8.50 Example (((S)-piperidin-3- (d, J = 6.8 Hz, 1H),8.33 (dd, J = 4.8, 2.0 29 yl)amino)pyrimidin-4- Hz, 1H), 7.92 (s, 1H),7.79-7.68 (m, yl)pyridin-2- 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 7.19-yl)oxy)phenyl)spiro[2.2]pentane- 7.10 (m, 1H), 4.64 (s, 1H), 3.71-3.631-carboxamide (m, 1H), 3.44-3.36 (m, 1H), 3.19-3.05 hydrochloride (m,2H), 2.29-2.20 (m, 2H), 2.16-2.08 (m, 1H), 2.05-1.85 (m, 2H), 1.59-1.54(m, 1H), 1.45 (dd, J = 7.2, 3.6 Hz, 1H), 1.06-0.87 (m, 4H). 152(S)-N-(2,6-difluoro-4-((3-(2- 553.2 (400 MHz, CD₃OD) δ 8.77 (s, 1H),8.49 Example (piperidin-3- (d, J = 6.4 Hz, 1H), 8.42-8.40 (m, 1H), 27ylamino)pyrimidin-4- 7.86 (s, 1H), 7.53-7.36 (m, 6H), 7.11-yl)pyridin-2-yl)oxy)phenyl)- 7.04 (m, 2H), 4.63 (s, 1H), 4.52 (s, 2H),1-phenylmethanesulfonamide 3.68-3.61 (m, 1H), 3.41-3.37 (m, 1H),hydrochloride 3.11 (m, 2H), 2.29-2.09 (m, 2H), 1.93 (m, 2H). 153(S)-1-phenyl-N-(2,3,6- 571.2 (400 MHz, CD₃OD) δ 8.78 (s, 1H), 8.51Example trifluoro-4-((3-(2-(piperidin- (d, J = 6.5 Hz, 1H), 8.42-8.35(m, 1H), 30 3-ylamino)pyrimidin-4- 7.87 (s, 1H), 7.54-7.37 (m, 6H),7.31- yl)pyridin-2- 7.24 (m, 1H), 4.62 (s, 1H), 4.56 (s, 2H),yl)oxy)phenyl)methanesulfonamide 3.71-3.62 (m, 1H), 3.44-3.37 (m, 1H),hydrochloride 3.18-3.05 (m, 2H), 2.32-2.22 (m, 1H), 2.19-2.11 (m, 1H),2.06-1.84 (m, 2H). 154 (S)-N-(2,6-difluoro-3- 567.2 (300 MHz, CD₃OD) δ8.81 (d, J = 7.8 Hz, Example methyl-4-(3-(2-(piperidin-3- 1H), 8.51 (d,J = 6.6 Hz, 1H), 8.37 (dd, J = 27 ylamino)pyrimidin-4- 4.8, 1.9 Hz, 1H),7.92 (d, J = 6.6 Hz, yl)pyridin-2- 1H), 7.53-7.50 (m, 2H), 7.47-7.31 (m,yloxy)phenyl)(phenyl)methanesulfonamide 4H), 7.01 (dd, J = 10.2, 2.1 Hz,1H), 4.64 hydrochloride (s, 1H), 4.54 (s, 2H), 3.78-3.59 (m, 1H),3.43-3.39 (m, 1H), 3.17-3.06 (m, 2H), 2.39-2.11 (m, 2H), 2.09 (s, 3H),2.05- 1.77 (m, 2H). 155 (S)-N-(2,3-difluoro-5- 567.2 (400 MHz, CD₃OD) δ8.57 (d, J = 7.2 Hz, Example methyl-4-((3-(2-(piperidin- 1H), 8.39 (d, J= 5.2 Hz, 1H), 8.15 (dd, J = 27 3-ylamino)pyrimidin-4- 4.9, 1.9 Hz, 1H),7.47-7.38 (m, 3H), yl)pyridin-2-yl)oxy)phenyl)- 7.39-7.32 (m, 3H), 7.28(dd, J = 7.6, 4.8 1-phenylmethanesulfonamide Hz, 1H), 7.05 (dd, J = 8.1,1.8 Hz, 1H), 4.47 (s, 2H), 4.26-4.08 (m, 1H), 3.40 (dd, J = 12.0, 3.9Hz, 1H), 3.12-3.07 (m, 1H), 2.86-2.66 (m, 2H), 2.25-2.10 (m, 1H), 2.08(s, 3H), 1.96-1.91 (m, 1H), 1.83-1.57 (m, 2H). 156(S)-1-phenyl-N-(2,3,5- 571.2 (400 MHz, CD₃OD) 8.66 (d, J = 7.7 Hz,Example trifluoro-4-((3-(2-(piperidin- 1H), 8.48 (d, J = 5.9 Hz, 1H),8.31 (d, J = 30 3-ylamino)pyrimidin-4- 3.8 Hz, 1H), 7.65 (s, 1H),7.45-7.33 (m, yl)pyridin-2- 6H), 7.13-7.04 (m, 1H), 4.57 (s, 2H),yl)oxy)phenyl)methanesulfonamide 4.48 (s, 1H), 3.70-3.62 (m, 1H), 3.38(d, hydrochloride J = 12.6 Hz, 1H), 3.07 (t, J = 11.2 Hz, 2H), 2.23 (d,J = 12.3 Hz, 1H), 2.13- 2.11 (m, 1H), 1.91-1.80 (m, 2H). 157(S)-N-(3-methyl-4-((3-(2- 531.1 (400 MHz, CD₃OD) δ 8.57 (d, J = 7.2 Hz,Example (piperidin-3- 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 27ylamino)pyrimidin-4- 2.0 Hz, 1H), 7.43-7.39 (d, J = 5.2 Hz,yl)pyridin-2-yl)oxy)phenyl)- 1H), 7.37 (m, 5H), 7.25 (d, J = 7.6, 1H),1-phenylmethanesulfonamide 7.12 (d, J = 7.2 Hz, 2H), 7.05-6.99 (m, 1H),4.43 (s, 2H), 4.09 (s, 1H), 3.32 (d, J = 12.4 Hz, 1H), 3.02 (d, J = 12.4Hz, 1H), 2.74-2.57 (m, 2H), 2.13-2.05 (m, 4H), 1.86 (d, J = 12.0 Hz,1H), 1.67 (s, 1H), 1.66-1.57 (m, 1H). 158 (S)-N-(2-fluoro-5-methyl-4-549.2 (400 MHz, CD₃OD) δ 8.56 (d, J = 12 Hz, Example (3-(2-(piperidin-3-1H), 8.35 (d, J = 8 Hz, 1H), 8.18-8.16 27 ylamino)pyrimidin-4- (m, 1H),7.44-7.40 (m, 2H), 7.38-7.33 yl)pyridin-2- (m, 4H), 7.29-7.24 (m, 2H),6.95 (d, J = yloxy)phenyl)(phenyl)methanesulfonamide 10.9 Hz, 1H), 4.45(s, 2H), 4.06 (s, 1H), 3.29 (d, J = 4.0 Hz, 1H), 2.98 (d, J = 12.8 Hz,1H), 2.69-2.53 (m, 2H), 2.12-2.05 (m, 5H), 1.87-1.80 (m, 1H), 1.71-1.52(m, 1H). 159 (S)-N-(3-fluoro-4-((3-(2- 535.2 (400 MHz, CD₃OD) δ 8.55 (d,J = 7.5 Hz, Example (piperidin-3- 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.16(dd, J = 27 ylamino)pyrimidin-4- 4.9, 2.0 Hz, 1H), 7.38-7.34 (m, 6H),yl)pyridin-2-yl)oxy)phenyl)- 7.32-6.98(m, 4H), 4.44 (s, 2H), 4.05 (s,1-phenylmethanesulfonamide 1H), 3.35-3.28 (m, 1H), 2.99-2.95 (m, 1H),2.67-2.52 (m, 2H), 2.12 (d, J = 11.4 Hz, 1H), 1.82-1.59 (m, 3H). 160(S)-N-(2,3-difluoro-6- 567.2 (300 MHz, CD₃OD) δ 8.58 (dd, J = 7.6,Example methyl-4-((3-(2-(piperidin- 1.9 Hz, 1H), 8.38 (d, J = 5.2 Hz,1H), 27 3-ylamino)pyrimidin-4- 8.15 (dd, J = 4.9, 1.9 Hz, 1H), 7.51-7.20yl)pyridin-2-yl)oxy)phenyl)- (m, 7H), 7.06 (dd, J = 8.1, 2.2 Hz, 1H),1-phenylmethanesulfonamide 4.45 (s, 2H), 4.21-4.06 (m, 1H), 3.39- 3.35(m, 1H), 3.15-2.98 (m, 1H), 2.86- 2.55 (m, 2H), 2.24-1.99 (m, 4H), 1.99-1.83 (m, 1H), 1.81-1.54 (m, 2H). 161 (S)-N-(2-chloro-3-fluoro-4- 569.1(400 MHz, DMSO-d₆) 8.60-8.42 (brs, Example ((3-(2-(piperidin-3- 2H),8.22 (dd, J = 4.8, 2.0 Hz, 1H), 8.07 34 ylamino)pyrimidin-4- (br, 1H),7.41-7.16 (m, 9H), 7.02 (t, J = yl)pyridin-2-yl)oxy)phenyl)- 9.1 Hz,1H), 4.11 (s, 3H), 3.34 (d, J = 1-phenylmethanesulfonamide 12.0 Hz, 2H),3.10 (d, J = 12.7 Hz, 1H), 2.84-2.62 (m, 2H), 1.97 (d, J = 11.6 Hz, 1H),1.85 (d, J = 12.8 Hz, 1H), 1.71- 1.52 (m, 2H). 162N-(2,3-difluoro-4-((3-(2- 585.2 (300 MHz, CD₃OD) δ 8.51 (d, J = 7.5 Hz,Example (((3S,5R)-5-fluoro-5- 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.19 (dd, J= 42 methylpiperidin-3- 4.9, 1.9 Hz, 1H), 7.52-7.21 (m, 8H),yl)amino)pyrimidin-4- 7.14-6.94 (m, 1H), 4.50 (s, 2H), 4.27 (s,yl)pyridin-2-yl)oxy)phenyl)- 1H), 3.10-2.71 (m, 4H), 2.18-2.00 (m,1-phenylmethanesulfonamide 2H), 1.40 (d, J = 21.9 Hz, 3H). 163(S)-N-(2-cyano-3-fluoro-4- 560.2 (300 MHz, CD₃OD) 8.73 (d, J = 7.7 Hz,Example ((3-(2-(piperidin-3- 1H), 8.48 (d, J = 6.5 Hz, 1H), 8.33 (dd, J= 27 ylamino)pyrimidin-4- 4.8, 1.8 Hz, 1H), 7.83 (d, J = 6.5 Hz,yl)pyridin-2-yl)oxy)phenyl)- 1H), 7.55 (t, J = 8.8 Hz, 1H), 7.51-7.321-phenylmethanesulfonamide (m, 6H), 7.25 (dd, J = 9.1, 1.6 Hz, 1H),hydrochloride 4.61 (s, 3H), 3.66 (d, J = 12.3 Hz, 1H), 3.44-3.31 (m,1H), 3.16-3.00 (m, 2H), 2.26-2.11 (m, 2H), 1.97-1.87 (m, 2H). 164N-(2,6-difluoro-3-methyl-4- 581.2 (400 MHz, CD₃OD) δ 8.54 (d, J = 7.6Hz, Example ((3-(2-(((3S,5R)-5-methyl-3- 1H), 8.35 (d, J = 5.2 Hz, 1H),8.20 (dd, J = 36 piperidyl)amino)pyrimidin- 4.9, 1.9 Hz, 1H), 7.50 (dd,J = 7.4, 2.1 4-yl)-2-pyridyl)oxy)phenyl)- Hz, 2H), 7.45-7.24 (m, 5H),6.87 (dd, J = 1-phenyl- 10.3, 1.9 Hz, 1H), 4.48 (s, 2H), 4.11-4.01 (m,1H), methanesulfonamide 3.40-3.36 (m, 1H), 3.01 (d, J = 13.6 Hz, 1H),2.36 (t, J = 11.5 Hz, 1H), 2.28-2.11 (m, 2H), 2.07 (s, 3H), 1.84-1.73(m, 1H), 1.20-1.11 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H). 1651-phenyl-N-(2,3,6-trifluoro- 585.2 (300 MHz, CD₃OD) δ 8.52 (d, J = 8.2Hz, Example 4-((3-(2-(((3S,5R)-5-methyl- 1H), 8.37 (d, J = 5.2 Hz, 1H),8.20 (dd, J = 36 3-piperidyl)amino)pyrimidin- 4.8, 1.9 Hz, 1H), 7.50(dd, J = 7.5, 2.1 4-yl)-2- Hz, 2H), 7.41-7.26 (m, 5H), 7.07-6.97pyridyl)oxy)phenyl)methane (m, 1H), 4.41 (s, 2H), 4.15 (s, 1H), 3.50sulfonamide (d, J = 9.1 Hz, 1H), 3.10 (d, J = 10.4 Hz, 1H), 2.45 (t, J =11.6 Hz, 1H), 2.31 (t, J = 12.1 Hz, 1H), 2.17 (d, J = 12.9 Hz, 1H), 1.85(s, 1H), 1.23 (q, J = 12.1 Hz, 1H), 1.00 (d, J = 6.6 Hz, 3H). 166(S)-1-(4-cyanophcnyl)-N- 578.2 (400 MHz, DMSO-d₆) δ 8.71-8.30 (m,Example (2,3-difluoro-4-((3-(2- 3H), 8.24 (d, J = 6.4 Hz, 1H), 7.83 (d,J = 27 (piperidin-3- 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H),ylamino)pyrimidin-4- 7.47-7.53(m, 1H), 7.37-7.32 (m, 2H), yl)pyridin-2-7.23-7.18 (m, 1H), 7.11-7.06 (m, 1H), yl)oxy)phenyl)methanesulfonamide4.54(s, 2H), 4.22-4.11 (m, 1H), 3.43- 3.40 (m, 1H), 3.32-3.31 (m, 1H),3.21- 3.17 (m, 1H), 2.88-2.78 (m, 2H), 2.07- 1.88 (m, 2H), 1.72-1.59 (m,2H). 167 (S)-N-(2,3-difluoro-4-((3-(2- 539.2 (400 MHz, DMSO-d₆) δ8.45-8.42 (m, Example (pyrrolidin-3- 2H), 8.23 (dd, J = 4.8, 2.0 Hz,1H), 7.55 37 ylamino)pyrimidin-4- (d, J = 6.0 Hz, 1H), 7.35-7.24 (m,7H), yl)pyridin-2-yl)oxy)phenyl)- 7.18 (t, J = 8.9 Hz, 1H), 6.90 (t, J =8.7 1-phenylmethanesulfonamide Hz, 1H), 4.47 (d, J = 5.6 Hz, 1H), 4.13(s, 2H), 3.33-3.19 (m, 2H), 3.15-3.02 (m, 2H), 2.19-2.10 (m, 1H),1.98-1.90 (m, 1H) 168 N-(2,3-difluoro-4-((3-(2-((1- 567.2 (400 MHz,DMSO-d₆) δ 9.80 (s, 1H), 8.39 Example methylpiperidin-4- (d, J = 5.1 Hz,2H), 8.23 (dd, J = 4.8, 1.9 37 yl)amino)pyrimidin-4- Hz, 1H), 7.40-7.31(m, 6H), 7.27-7.09 yl)pyridin-2-yl)oxy)phenyl)- (m, 4H), 4.45 (s, 2H),3.81 (s, 1H), 2.87 1-phenylmethanesulfonamide (d, J = 11.3 Hz, 2H), 2.27(s, 3H), 2.18 (t, J = 11.7 Hz, 2H), 1.92 (d, J = 12.4 Hz, 2H), 1.64-1.54(m, 2H). 169 N-(4-((3-(2-(((1r,4r)-4- 567.2 (400 MHz, DMSO-d₆) δ8.39-8.26 (m, Example aminocyclohexyl)amino)pyrimidin- 2H), 8.21 (d, J =4.0 Hz, 1H), 7.48 (s, 38 4-yl)pyridin-2- 2H), 7.29-7.08 (m, 10H),6.84-6.80 yl)oxy)-2,3-difluorophenyl)- (m, 1H), 4.04 (s, 2H), 3.72 (s,1H), 2.93 (s, 1-phenylmethanesulfonamide 1H), 1.98-1.80 (m, 4H),1.38-1.19 (m, 4H). 170 (S)-N-(2,3-difluoro-4-((3-(2- 567.2 (300 MHz,CD₃OD) δ 8.61-8.55 (m, Example ((1-methylpiperidin-3- 1H), 8.37-8.35 (m,1H), 8.20-8.17 (m, 38 yl)amino)pyrimidin-4- 1H), 7.44-7.23 (m, 8H),7.06-6.99 (m, yl)pyridin-2-yl)oxy)phenyl)- 1H), 4.50 (s, 2H), 4.26-4.15(m, 1H), 1-phenylmethanesulfonamide 3.16-3.10 (m, 1H), 2.82-2.70 (m,1H), 2.35 (s, 3H), 2.20-1.99 (m, 3H), 1.85- 1.76 (m, 2H), 1.53-1.36 (m,1H). 171 N-(4-((3-(2-((2- 513.2 (400 MHz, DMSO-d₆) δ 8.56-8.43 (m,Example aminoethyl)amino)pyrimidin- 2H), 8.32-8.31 (m, 1H), 7.64-7.55(m, 38 4-yl)pyridin-2-yl)oxy)-2,3- 1H), 7.45-7.37 (m, 6H), 7.25-7.17 (m,difluorophenyl)-1- 2H), 4.56 (s, 2H), 3.82-3.61 (m, 2H),phenylmethanesulfonamide 3.15-3.08 (m, 2H). 172N-(2,3-difluoro-4-((3-(2-(2- 527.1 (400 MHz, CD₃OD) δ 8.53-8.51 (m,Example (methylamino)ethylamino)pyrimidin- 1H), 8.36 (d, J = 5.6 Hz,1H), 8.18-8.16 38 4-yl)-2-pyridyl)oxy)phenyl)-1- (m, 1H), 7.41-7.40 (m,3H), 7.39- phenyl-methanesulfonamide 7.31(m, 3H), 7.28-7.20 (m, 2H),6.92- 6.88 (m, 1H), 4.40 (s, 2H), 3.72-3.61 (m, 2H), 3.04 (t, J = 6.0Hz, 2H), 2.49 (s, 3H). 173 (S)-1-cyclobutyl-N-(2,3- 531.2 (400 MHz,CD₃OD) δ 8.55 (d, J = 7.8 Hz, Example difluoro-4-((3-(2-(piperidin- 1H),8.36 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 27 3-ylamino)pyrimidin-4- 7.8 Hz,1H), 7.39-7.28(m, 3H), 7.10- yl)pyridin-2- 7.06 (m, 1H), 4.12-4.03 (m,1H), 3.38- yl)oxy)phenyl)methanesulfonamide 3.34 (m, 1H), 3.26 (d, J =6.6 Hz, 2H), 3.05-3.02 (m, 1H), 2.95-2.85 (m, 1H), 2.72-2.60 (m, 2H),2.24-1.64 (m, 10H). 174 N-(2,3-difluoro-4-((3-(2- 585.2 (400 MHz, CD₃OD)δ 8.55 (d, J = 7.6 Hz, Example (((3S,5S)-5-fluoro-5- 1H), 8.36 (d, J =5.2 Hz, 1H), 8.19 (dd, J = 42 methylpiperidin-3- 4.9, 1.9 Hz, 1H),7.44-7.34 (m, 6H), yl)amino)pyrimidin-4- 7.32-7.23 (m, 2H), 7.06-7.00(m, 1H), yl)pyridin-2-yl)oxy)phenyl)- 4.50 (s, 2H), 4.35 (s, 1H), 3.36(s, 1H), 1-phenylmethanesulfonamide 3.01 (m, 1H), 2.62 (dd, J = 34.8,14.1 Hz, 1H), 2.41-2.34 (m, 2H), 1.74-1.56 (m, 1H), 1.36 (d, J = 20.9Hz, 3H). 175 (S)-N-(6-fluoro-2,3- 563.3 (400 MHz, CD₃OD) δ 8.56 (d, J =7.4 Hz, Example dimethyl-4-((3-(2-(piperidin- 1H), 8.35 (d, J = 5.2 Hz,1H), 8.16 (dd, J = 27 3-ylamino)pyrimidin-4- 4.9, 2.0 Hz, 1H), 7.47 (dd,J = 7.1, 2.6 yl)pyridin-2-yl)oxy)phenyl)- Hz, 2H), 7.40-7.36 (m, 4H),7.28 (dd, J = 1-phenylmethanesulfonamide 7.6, 4.9 Hz, 1H), 6.89 (d, J =10.4 Hz, 1H), 4.46 (s, 2H), 4.05 (s, 1H), 3.32-3.27 (m, 1H), 2.97 (d, J= 12.6 Hz, 1H), 2.65-2.52 (m, 2H), 2.39 (s, 3H), 2.11 (s, 1H), 2.09 (s,3H), 1.81-1.80 (m, 1H), 1.66-1.55 (m, 2H). 1761-phenyl-N-(2,3,6-trifluoro- 589.2 (400 MHz, CD₃OD) 8.58 (d, J = 7.0 Hz,Example 4-((3-(2-(((3S,5S)-5- 1H), 8.22 (dd, J = 4.9, 1.9 Hz, 1H), 7.5240 fluoropiperidin-3- (d, J = 2.4 Hz, 1H), 7.53-7.50 (m, 2H),yl)amino)pyrimidin-4- 7.43-7.33 (m, 5H), 7.21-7.16 (m, 1H),yl)pyridin-2- 4.98-4.87 (m, 1H), 4.52 (s, 2H), 4.47-yl)oxy)phenyl)methanesulfonamide 4.35 (m, 1H), 3.37 (s, 1H), 3.19 (t, J= 13.3 Hz, 1H), 2.85 (dd, J = 37.2, 14.1 Hz, 1H), 2.62-2.51 (m, 1H),2.49-2.36 (m, 1H), 1.94-1.74 (m, 1H). 177 N-(2,3-difluoro-5-methyl-4-581.2 (400 MHz, CD₃OD) δ 8.56 (d, J = 8.0 Hz, Example((3-(2-(((3S,5R)-5-methyl-3- 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.16-8.14 36piperidyl)amino)pyrimidin- (m, 1H), 7.46-7.35 (m, 6H), 7.29-7.284-yl)-2-pyridyl)oxy)phenyl)- (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.46 (s,1-phenyl- 2H), 4.11-4.05 (m, 1H), 3.41-3.35 (m, methanesulfonamide 1H),3.04-3.01 (m, 1H), 2.38-2.35 (m, 1H), 2.28-2.16 (m, 2H), 2.09 (s, 3H),1.85-1.70 (m, 1H), 1.23-1.14 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). 178N-(2,3-difluoro-4-((3-(2- 585.2 (400 MHz, CD₃OD) δ 8.60 (d, J = 8.0 Hz,Example (((3S,5S)-5-fluoro-3- 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.16-8.1440 piperidyl)amino)pyrimidin- (m, 1H), 7.46-7.35 (m, 6H), 7.31-7.284-yl)-2-pyridyl)oxy)-5- (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.95-methyl-phenyl)-1-phenyl- 4.80 (m, 1H), 4.51 (s, 2H), 4.40-4.37methanesulfonamide (m, 1H), 3.36-3.35 (m, 1H), 3.17-3.10 (m, 1H),2.87-2.74 (m, 1H), 2.56-2.35 (m, 2H), 2.09 (s, 3H), 1.89-1.79 (m, 1H).179 N-(2,6-difluoro-4-((3-(2- 585.2 (400 MHz, CD₃OD) δ 8.57 (d, J = 7.5Hz, Example (((3S,5S)-5-fluoro-3- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.20(dd, J = 40 piperidyl)amino)pyrimidin- 4.9, 2.0 Hz, 1H), 7.50 (dd, J =7.3, 2.4 4-yl)-2-pyridyl)oxy)-3- Hz, 2H), 7.43-7.30 (m, 5H), 6.91 (dd, J= methyl-phenyl)-1-phenyl- 10.4, 2.0 Hz, 1H), 4.95-4.80 (m,methanesulfonamide 1H), 4.51 (s, 2H), 4.37 (s, 1H), 3.28 (s, 1H), 3.13(t, J = 12.6 Hz, 1H), 2.79 (dd, J = 36.4, 14.0 Hz, 1H), 2.52 (t, J =11.5 Hz, 1H), 2.45-2.32 (m, 1H), 2.08 (d, J = 1.8 Hz, 3H), 1.90-1.75 (m,1H). 180 N-(2,3-difluoro-4-((3-(2-(4- 553.2 (400 MHz, DMSO-d₆) δ8.41-8.38 (m, Example piperidylamino)pyrimidin-4- 2H), 8.22 (dd, J =4.8, 1.9 Hz, 1H), 7.43 38 yl)-2-pyridyl)oxy)phenyl)-1- (d, J = 7.4 Hz,1H), 7.32-7.23 (m, 7H), phenyl-methanesulfonamide 7.17 (td, J = 9.0, 2.2Hz, 1H), 6.88 (td, J = 9.0, 2.1 Hz, 1H), 4.12 (s, 2H), 4.02-4.00 (m,1H), 3.21-3.17 (m, 2H), 2.88 (td, J = 12.3, 3.0 Hz, 2H), 2.02 (d, J =13.1 Hz, 2H), 1.68-1.58 (m, 2H). 181 (S)-N-(2,3-difluoro-4-((3-(2- 567.2(400 MHz, CD₃OD) δ 8.56 (d, J = 7.6 Hz, Example ((6-oxopiperidin-3- 1H),8.39 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 38 yl)amino)pyrimidin-4- 7.6 Hz,1H), 7.43-7.23(m, 8H), 7.05- yl)pyridin-2-yl)oxy)phenyl)- 7.02 (m, 1H),4.51 (s, 2H), 4.42-4.39 1-phenylmethanesulfonamide (m, 1H), 3.68-3.64(m, 1H), 3.30-3.27 (m, 1H), 2.58-2.43 (m, 2H), 2.22-2.12 (m, 1H),2.11-1.97 (m, 1H). 182 N-(2,3-difluoro-4-((3-(2- 568.1 (300 MHz,DMSO-d₆) 9.94 (s, 1H), 8.38 Example (((1r,4r)-4- (d, J = 5.2 Hz, 2H),8.28-8.18 (m, 1H), 38 hydroxycyclohexyl)amino)pyrimidin- 7.45-7.33 (m,6H), 7.24-7.12 (m, 4H), 4-yl)pyridin-2- 4.54 (d, J = 5.4 Hz, 3H), 3.74(s, 1H), yl)oxy)phenyl)-1- 3.42 (s, 1H), 1.96-1.80 (m, 4H), 1.34-phenylmethanesulfonamide 1.24 (m, 4H). 183 (S)-N-(4-((3-(2-((5,5- 589.1(400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 8.24 Example difluoropiperidin-3- (s,1H), 7.41-7.16 (m, 10H), 4.55 (s, 38 yl)amino)pyrimidin-4- 2H),4.13-4.00 (m, 1H), 3.10-3.00 (m, yl)pyridin-2-yl)oxy)-2,3- 2H),2.81-2.68 (m, 1H), 2.45-2.32 (m, difluorophenyl)-1- 2H), 2.07-1.96 (m,1H). phenylmethanesulfonamide 184 N-(4-((3-(2-((2- 541.3 (400 MHz,DMSO-d₆) δ 9.84 (s, 1H), 8.45 Example(dimethylamino)ethyl)amino)pyrimidin- (s, 1H), 8.40 (d, J = 5.2 Hz, 1H),8.23 (d, 38 4-yl)pyridin-2-yl)oxy)- J = 6.8, 1H), 7.42-7.35 (m, 6H),7.26 (d, 2,3-difluorophenyl)- J = 4.8 Hz, 1H), 7.23-7.12 (m, 3H), 4.481-phenylmethanesulfonamide (s, 2H), 3.48 (d, J = 6.4 Hz, 2H), 2.57 (d, J= 6.8 Hz, 2H), 2.28 (s, 6H). 185 N-(4-((3-(2-(3- 551.2 (300 MHz, CD₃OD)δ 8.56 (d, J = 7.0 Hz, Example azabicyclo[3.1.0]hexan-5- 1H), 8.39 (d, J= 5.2 Hz, 1H), 8.18 (dd, J = 41 ylamino)pyrimidin-4-yl)-2- 4.9, 1.9 Hz,1H), 7.44-7.24 (m, 8H), pyridyl)oxy)-2,3-difluoro- 7.02-7.00 (m, 1H),4.48 (s, 2H), 3.38 phenyl)-1-phenyl- (dd, J = 11.4, 3.7 Hz, 1H),3.31-3.23 (m, methanesulfonamide; 2H), 3.02 (d, J = 11.4 Hz, 1H), 1.76-Isomer 1 1.74 (m, 1H), 1.12-1.10 (m, 1H), 1.04 (t, J = 5.5 Hz, 1H). 186N-(4-((3-(2-(3- 551.2 (300 MHz, CD₃OD) δ 8.56 (d, J = 7.0 Hz, Exampleazabicyclo[3.1.0]hexan-5- 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.18 (dd, J =41 ylamino)pyrimidin-4-yl)-2- 4.9, 1.9 Hz, 1H), 7.44-7.24 (m, 8H),pyridyl)oxy)-2,3-difluoro- 7.02-7.00 (m, 1H), 4.48 (s, 2H), 3.38phenyl)-1-phenyl- (dd, J = 11.4, 3.7 Hz, 1H), 3.31-3.23 (m,methanesulfonamide; 2H), 3.02 (d, J = 11.4 Hz, 1H), 1.76- Isomer 2 1.74(m, 1H), 1.12-1.10 (m, 1H), 1.04 (t, J = 5.5 Hz, 1H). 187(S)-1-(2-cyanophenyl)-N- 578.2 (300 MHz, CF₃COOD) δ 9.27 (d, J = 7.2Example (2,3-difluoro-4-((3-(2- Hz, 1H), 8.72 (d, J = 6.6 Hz, 1H), 8.57(d, 27 (piperidin-3- J = 5.1 Hz, 1H), 7.97-7.90 (m, 2H), 7.87-ylamino)pyrimidin-4- 7.82 (m, 3H), 7.78-7.67 (m, 2H), 7.49 yl)pyridin-2-(t, J = 8.1 Hz, 1H), 4.94 (d, J = 8.7 Hz,yl)oxy)phenyl)methanesulfonamide 3H), 3.92 (d, J = 12.0 Hz, 1H), 3.66(d, J = 11.7 Hz, 1H), 3.57-3.53 (m, 1H), 3.41- 3.38 (m, 1H), 2.44-2.40(m, 1H), 2.29 (s, 1H), 2.20-2.07 (m, 2H). 188(S)-N-(2,3-difluoro-4-((3-(2- 535.2 (400 MHz, DMSO-d₆) δ 8.41 (d, J =5.1 Example (piperidin-3- Hz, 2H), 8.22 (dd, J = 4.8, 1.9 Hz, 1H), 27ylamino)pyrimidin-4- 7.85 (brs, 1H), 7.33-7.28 (m, 3H), 7.18yl)pyridin-2-yl)oxy)phenyl)-1-(1- (t, J = 8.8 Hz, 1H), 6.94 (t, J = 8.9Hz, fluorocyclopropyl)methanesulfonamide 1H), 4.05 (s, 1H), 3.47 (d, J =20.9 Hz, 2H), 3.33-3.26 (m, 1H), 3.02 (s, 1H), 2.66 (d, J = 10.6 Hz,2H), 1.96 (s, 1H), 1.79 (s, 1H), 1.57 (d, J = 9.2 Hz, 2H), 1.12-0.79 (m,4H). 189 2.2-difluoro-N-(2,3,6- 591.1 (300 MHz, CD₃OD) δ 8.77 (s, 1H),8.53 Example trifluoro-4-((3-(2-(((3S,5S)- (d, J = 6.3 Hz, 1H), 8.37 (d,J = 4.8 Hz, 40 5-fluoro-3- 1H), 7.90 (s, 1H), 7.49-7.42 (m, 1H),piperidyl)amino)pyrimidin- 7.35-7.24 (m, 1H), 5.43-5.18 (m, 1H),4-yl)-2- 3.99-3.86 (m, 2H), 3.81-3.63 (m, 2H),pyridyl)oxy)phenyl)butane- 3.52-3.41 (m, 1H), 3.31-3.28 (m, 1H),1-sulfonamide 3.15 (s, 1H), 2.64 (s, 1H), 2.29-1.96 (m, 3H), 1.12-1.03(m, 3H). 190 1-phenyl-N-(2,3,6-trifluoro- 603.1 (300 MHz, CD₃OD) δ 8.69(s, 1H), 8.50- Example 4-((3-(2-(((3S,5S)-5-fluoro- 8.48 (m, 1H), 8.33(s, 1H), 7.71 (s, 1H), 42 5-methyl-3- 7.56-7.48 (m, 2H), 7.48-7.37 (m,4H), piperidyl)amino)pyrimidin- 7.29-7.18 (m, 1H), 4.88 (s, 2H), 3.79-4-yl)-2- 3.67 (m, 1H), 3.61-3.47 (m, 1H), 3.41-pyridyl)oxy)phenyl)methane 3.37 (m, 1H), 3.29-3.15(m, 1H), 3.03-sulfonamide 2.89 (m, 1H), 2.55-2.43 (m, 1H), 2.15- 1.88 (m, 1H),2.51-2.48 (m, 3H). 191 1-(4-cyanophenyl)-N-(2,3,6- 614.1 (300 MHz,CD₃OD) δ 8.72 (s, 1H), 8.51 Example trifluoro-4-((3-(2-(((3S,5S)- (d, J= 6.6 Hz, 1H), 8.36 (s, 1H), 7.84-7.67 (m, 5H), 40 5-fluoropiperidin-3-7.45 (d, J = 5.7 Hz, 1H), yl)amino)pyrimidin-4- 7.32-7.23 (m, 1H),5.45-5.09 (m, 1H), yl)pyridin-2- 4.68 (s, 2H), 3.78-3.64 (m, 2H), 3.41-yl)oxy)phenyl)methanesulfonamide 3.36 (m, 1H), 3.31-3.28 (m, 1H), 3.21-3.02 (m, 1H), 2.19 (s, 1H), 2.05 (s, 1H). 192 N-(2,3-difluoro-4-((3-(2-567.2 (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.49 Example (((S)-piperidin-3-(d, J = 6.2 Hz, 1H), 8.32 (s, 1H), 7.80 (s, 27 yl)amino)pyrimidin-4-1H), 7.45-7.39 (m, 2H), 7.19 (t, J = 8.8 yl)pyridin-2-yl)oxy)phenyl)-Hz, 1H), 4.56 (s, 1H), 3.69-3.65 (m, 1-(2,2- 1H), 3.55-3.52 (m, 1H),3.38-3.34 (m, difluorocyclobutyl)methanesulfonamide 3H), 3.13-3.09 (m,2H), 2.61-2.47 (m, hydrochloride 2H), 2.27-2.13 (m, 3H), 1.98-1.69 (m,3H). 193 1-phenyl-N-(2,3,6-trifluoro- 589.2 (400 MHz, CD₃OD) δ 8.74 (d,J = 7.6 Hz, Example 4-((3-(2-(((3R,5R)-5-fluoro- 1H), 8.52 (d, J = 6.3Hz, 1H), 8.37 (d, J = 30 3-piperidyl)amino)pyrimidin- 4.2 Hz, 1H), 7.85(s, 1H), 7.54-7.40 (m, 4-yl)-2- 6H), 7.31-7.24 (m, 1H), 5.31 (d, J =pyridyl)oxy)phenyl)methane 44.8 Hz, 1H), 4.56 (s, 2H), 3.77-3.66sulfonamide (m, 2H), 3.47-3.42 (m, 1H), 3.35-3.31 (m, 1H), 3.13 (t, J =11.8 Hz, 1H), 2.63 (s, 1H), 2.15 (dt, J = 42.7, 13.3 Hz, 1H). 194(S)-2,2-difluoro-N-(2,3,6- 573.2 (400 MHz, CD₃OD) δ 8.47 (dd, J = 7.6,Example trifluoro-4-((3-(2-(piperidin- 2.0 Hz, 1H), 8.39 (d, J = 5.3 Hz,1H), 30 3-ylamino)pyrimidin-4- 8.19 (dd, J = 4.9, 2.0 Hz, 1H), 7.36 (d,J = yl)pyridin-2- 5.3 Hz, 1H), 7.28 (dd, J = 7.6, 4.8 Hz,yl)oxy)phenyl)butane-1- 1H), 6.94-6.88 (m, 1H), 4.21 (s, 1H),sulfonamide 3.66 (t, J = 13.5 Hz, 2H), 3.53 (s, 1H), 3.27-3.21 (s, 1H),2.99-2.88 (m, 2H), 2.28-2.13 (m, 3H), 2.02 (s, 1H), 1.86- 1.70 (m, 2H),1.07 (t, J = 7.5 Hz, 3H). 195 (S)-1-(5-methylisoxazol-3- 576.2 (300 MHz,DMSO-d₆) δ 8.43 (d, J = 5.1 Example yl)-N-(2,3,6-trifluoro-4-((3- Hz,3H), 8.33-8.23 (m, 1H), 7.45 (d, J = 30 (2-(piperidin-3- 7.2 Hz, 1H),7.39-7.28 (m, 2H), 7.05 (t, ylamino)pyrimidin-4- J = 8.8 Hz, 1H), 6.32(d, J = 1.1 Hz, 1H), yl)pyridin-2- 4.15 (brs, 1H), 4.04 (s, 2H), 3.42(s, 2H), yl)oxy)phenyl)methanesulfonamide 3.17 (d, J = 12.3 Hz, 1H),2.92-2.68 (m, 2H), 2.38 (d, J = 0.9 Hz, 3H), 2.07-1.82 (m, 2H),1.74-1.59 (m, 2H). 196 (S)-N-(2,3,6-trifluoro-4-((3- 640.2 (300 MHz,CD₃OD) δ 8.81 (s, 1H), 8.49 Example (2-(piperidin-3- (dd, J = 7.6, 1.9Hz, 1H), 8.40 (d, J = 5.3 30 ylamino)pyrimidin-4- Hz, 1H), 8.23-8.14 (m,2H), 7.82 (d, J = yl)pyridin-2-yl)oxy)phenyl)- 8.0 Hz, 1H), 7.38 (d, J =5.2 Hz, 1H), 1-(6-(trifluoromethyl)pyridin-3- 7.29 (dd, J = 7.6, 4.9 Hz,1H), 6.97-6.85 yl)methanesulfonamide (m, 1H), 4.45 (s, 2H), 4.22 (s,1H), 3.53 (d, J = 13.0 Hz, 1H), 3.25-3.21 (m, 1H), 2.94 (t, J = 11.0 Hz,2H), 2.17-2.14 (m, 1H), 2.05-2.03 (m, 1H), 1.95-1.63 (m, 2H). 197(S)-N-(2-fluoro-3-((3-(2- 463.2 (400 MHz, CD₃OD) δ 8.54 (d, J = 7.6 Hz,Example (piperidin-3- 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.19-8.08 43ylamino)pyrimidin-4- (m, 1H), 7.38 (d, J = 5.6 Hz, 1H), 7.30-yl)pyridin-2- 7.16 (m, 4H), 4.47 (s, 2H), 4.05 (s, 1H),yl)oxy)benzyl)cyclopropane 3.29 (s, 1H), 2.96 (d, J = 12.4 Hz, 1H),carboxamide 2.67-2.58 (m, 1H), 2.59-2.48 (m, 1H), 2.11 (d, J = 12.4 Hz,1H), 1.86-1.78 (m, 1H), 1.69-1.51 (m, 3H), 0.98-0.88 (m, 2H), 0.85-0.74(m, 2H). 198 1-phenyl-N-(2,3,6-trifluoro- 570.2 (400 MHz, CDCl₃) δ 8.70(d, J = 2.3 Hz, Example 4-((3-(2-(piperidin-3- 1H), 8.48 (d, J = 5.4 Hz,1H), 8.03 (d, J = 44 ylmethyl)pyrimidin-4- 4.1 Hz, 1H), 7.92 (d, J = 5.4Hz, 1H), yl)pyridin-2- 7.54-7.47 (m, 2H), 7.38-7.33 (m, 3H),yl)oxy)phenyl)methanesulfonamide 7.02-6.99 (m, 1H), 6.53-6.51 (m, 1H),4.35 (s, 2H), 3.16 (d, J = 12.2 Hz, 1H), 3.05 (d, J = 13.3 Hz, 2H), 2.68(t, J = 12.0 Hz, 1H), 2.41-2.30 (m, 3H), 2.27-2.24 (m, 2H), 1.85 (d, J =12.7 Hz, 1H), 1.57- 1.43 (m, 2H), 1.17 (d, J = 13.2 Hz, 1H). 1991-phenyl-N-(2,3,6-trifluoro- 570.2 (300 MHz, CD₃OD) 8.80 (d, J = 5.4 Hz,Example 4-((3-(2-(piperidin-3- 1H), 8.61 (dd, J = 2.6, 1.9 Hz, 1H), 8.2444 ylmethyl)pyrimidin-4- (dd, J = 4.9, 1.9 Hz, 1H), 8.07 (d, J = 5.4yl)pyridin-2- Hz, 1H), 7.54-7.45 (m, 2H), 7.47-7.27yl)oxy)phenyl)methanesulfonamide (m, 4H), 6.94-6.87 (m, 1H), 4.34 (s,2H), 3.32 (s, 1H), 3.21 (d, J = 12.5 Hz, 1H), 3.02-3.00 (m, 2H),2.87-2.63 (m, 2H), 2.45 (d, J = 11.3 Hz, 1H), 1.90- 1.84 (m, 2H),1.83-1.67 (m, 1H), 1.45- 1.31 (m, 1H). 200 1,1,1-trifluoro-3-((2-fluoro-493.2 (300 MHz, CD₃OD) δ 8.54 (d, J = 2.5 Hz, Example3-((3-(2-(((S)-piperidin-3- 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.13 (dd, J =45 yl)amino)pyrimidin-4- 4.9, 2.0 Hz, 1H), 7.38 (d, J = 5.3 Hz,yl)pyridin-2- 1H), 7.26 (dd, J = 2.6, 4.9 Hz, 1H), 7.06yl)oxy)phenyl)amino)propan- (td, J = 8.2, 1.8 Hz, 1H), 6.73 (t, J = 7.42-ol Hz, 1H), 6.61-6.49 (m, 1H), 4.24-4.16 (m, 1H), 4.11-4.01 (m, 1H),3.66-3.55 (m, 1H), 3.39-3.36 (m, 1H), 3.31-3.28 (m, 1H), 3.05-2.91 (m,1H), 2.73-2.49 (m, 2H), 2.13 (s, 1H), 1.82 (s, 1H), 1.73-1.50 (m, 2H).201 1,1,1-trifluoro-3-((2-fluoro- 493.2 (300 MHz, CD₃OD) δ 8.54 (d, J =7.7 Hz, Example 3-((3-(2-(((S)-piperidin-3- 1H), 8.34 (d, J = 5.3 Hz,1H), 8.13 (dd, J = 45 yl)amino)pyrimidin-4- 4.9, 2.0 Hz, 1H), 7.38 (d, J= 5.3 Hz, yl)pyridin-2- 1H), 7.26 (dd, J = 7.6, 4.9 Hz, 1H), 7.06yl)oxy)phenyl)amino)propan- (td, J = 8.2, 1.9 Hz, 1H), 6.73 (t, J = 7.62-ol Hz, 1H), 6.56 (t, J = 6.9 Hz, 1H), 4.24- 4.14 (m, 1H), 4.10-4.00(m, 1H), 3.64- 3.52 (m, 1H), 3.37-3.35 (m, 1H), 3.31- 3.27 (m, 1H),3.00-2.96 (d, J = 12.5 Hz, 1H), 2.75-2.50 (m, 2H), 2.17-2.08 (m, 1H),1.82 (s, 1H), 1.73-1.54 (m, 2H). 202 1-cyclobutyl-N-(2,3,6- 581.2 (300MHz, CD₃OD) δ 8.56 (d, J = 7.5 Hz, Example trifluoro-4-((3-(2-(((3S,5S)-1H), 8.37 (d, J = 5.1 Hz, 1H), 8.27-8.16 42 5-fluoro-5-methylpiperidin-(m, 1H), 7.40-7.31 (m, 2H), 7.21-7.10 3-yl)amino)pyrimidin-4- (m, 1H),4.36 (s, 1H), 3.39-3.34 (m, yl)pyridin-2- 3H), 3.12-2.90 (m, 2H),2.75-2.55 (m, yl)oxy)phenyl)methanesulfonamide 1H), 2.49-2.19 (m, 4H),2.09-1.82 (m, 4H), 1.79-1.52(m, 1H), 1.42-1.30 (m, 3H). 2031-(5-methylisoxazol-3-yl)- 608.2 (400 MHz, CD₃OD) δ 8.55 (d, J = 7.6 Hz,Example N-(2,3,6-trifluoro-4-((3-(2- 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.20(dd, J = 42 (((3S,5S)-5-fluoro-5- 4.8, 2.0 Hz, 1H), 7.37 (d, J = 5.2 Hz,methylpiperidin-3- 1H), 7.32 (dd, J = 7.6, 4.8 Hz, 1H), 7.12-yl)amino)pyrimidin-4- 7.08 (m, 1H), 6.38 (d, J = 1.2 Hz, 1H),yl)pyridin-2- 4.51 (s, 2H), 4.44 (s, 1H), 3.51-3.42 (m,yl)oxy)phenyl)methanesulfonamide 1H), 3.23-3.13 (m, 1H), 2.90-2.82 (m,1H), 2.77 (d, J = 14.0 Hz, 1H), 2.52- 2.45 (m, 3H), 2.43-2.34 (m, 1H),1.84- 1.63 (m, 1H), 1.47-1.36(s, 3H). 204 1-(5-methylisoxazol-3-yl)-594.1 (400 MHz, CD₃OD) δ 8.56 (d, J = 7.6 Hz, ExampleN-(2,3,6-trifluoro-4-((3-(2- 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.20 (dd, J= 40 (((3S,5S)-5-fluoropiperidin- 4.2, 2.0 Hz, 1H), 7.40-7.29 (m, 2H),3-yl)amino)pyrimidin-4- 7.09 (dd, J = 9.6, 7.2 Hz, 1H), 6.38 (d, J =yl)pyridin-2- 1.0 Hz, 1H), 5.09-5.01 (m, 1H), 4.59-yl)oxy)phenyl)methanesulfonamide 4.49 (m, 3H), 3.44 (d, J = 12.8 Hz,1H), 3.27 (d, J = 12.4 Hz, 1H), 2.99-2.90 (m, 1H), 2.69-2.60 (m, 1H),2.49-2.41 (m, 4H), 1.94-1.88 (m, 1H). 205 3,3,3-trifluoro-N-(2,3,6-595.1 (300 MHz, CD₃OD) δ 8.55 (d, J = 5.1 Hz, Exampletrifluoro-4-((3-(2-(((3S,5S)- 1H), 8.38 (d, J = 5.4 Hz, 1H), 8.20 (dd, J= 40 5-fluoro-3- 1.8 Hz, 3.0 Hz, 1H), 7.37 (d, J = 5.1 Hz,piperidyl)amino)pyrimidin- 1H), 7.34 (d, J = 5.1 Hz, 1H), 7.15- 4-yl)-2-7.08(m, 1H), 5.07-4.91(m, 1H), 4.51- pyridyl)oxy)phenyl)propane- 4.36(m, 1H), 3.46-3.34 (m, 3H), 3.29- 1-sulfonamide 3.25 (m, 1H), 3.03-2.78(m, 3H), 2.68- 2.60 (m, 1H), 2.49-2.38 (m, 1H), 1.95- 1.80 (m, 1H). 206(S)-N-(2,3-difluoro-4-((3-(2- 575.1 (400 MHz, DMSO-d₆) δ 8.52 (s, 2H),8.41 Example (piperidin-3- (d, J = 5.1 Hz, 2H), 8.19 (dd, J = 4.8, 2.046 ylamino)pyrimidin-4- Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.39-yl)pyridin-2-yl)oxy)phenyl)- 7.24 (m, 5H), 7.06-6.86 (m, 1H), 6.82-3,5-difluorobenzenesulfonamide 6.66 (m, 1H), 4.17 (d, J = 8.4 Hz, 1H),3.50-3.36 (m, 1H), 3.23-3.11 (m, 1H), 2.97-2.75 (m, 2H), 2.06-1.87 (m,2H), 1.77-1.56 (m, 2H). 207 (S)-N-(2,3-difluoro-4-((3-(2- 623.1 (400MHz, DMSO- d₆) δ 8.62-8.25 (m, Example (piperidin-3- 1H), 8.18 (dd, J =4.8, 2.0 Hz, 1H), 7.73 46 ylamino)pyrimidin-4- (dt, J = 7.7, 1.3 Hz,1H), 7.61-7.58 (m, yl)pyridin-2-yl)oxy)phenyl)-3- 1H), 7.55 (t, J = 8.0Hz, 1H), 7.45-7.36 (trifluoromethoxy)benzenesulfonamide (m, 2H),7.32-7.22 (m, 2H), 6.94 (td, J = 9.0, 2.2 Hz, 1H), 6.74 (t, J = 8.4 Hz,1H), 4.20-4.12 (m, 1H), 3.45-3.37 (m, 1H), 3.53-3.35 (m, 0H), 3.37 (s,0H), 3.21-3.13 (m, 1H), 2.92-2.71 (m, 2H), 2.01-1.93 (m, 1H), 1.93-1.82(m, 1H), 1.73- 1.54 (m, 2H). 208 (S)-N-(2,3-difluoro-4-((3-(2- 605.1(400 MHz, DMSO- d₆) δ 8.40 (t, J = 6.3 Example (piperidin-3- Hz, 3H),8.18 (dd, J = 4.8, 2.0 Hz, 1H), 46 ylamino)pyrimidin-4- 7.68-7.57 (m,1H), 7.49-7.34 (m, 4H), yl)pyridin-2-yl)oxy)phenyl)-3- 7.32-7.18 (m,4H), 6.94 (td, J = 9.0, 2.1 (difluoromethoxy)benzenesulfonamide Hz, 1H),6.79-6.70 (m, 1H), 3.20-3.08 (m, 1H), 2.97-2.63 (m, 3H), 2.06-1.81 (m,2H), 1.64 (dp, J = 30.8, 10.4, 9.5 Hz, 2H). 209(S)-N-(2,3-difluoro-4-((3-(2- 571.2 (400 MHz, DMSO- d₆) δ 8.43 (d, J =5.1 Example (piperidin-3- Hz, 1H), 8.23 (dd, J = 4.8, 1.9 Hz, 1H), 46ylamino)pyrimidin-4- 7.60-7.12 (m, 5H), 4.15 (s, 1H), 3.23 (d,yl)pyridin-2-yl)oxy)phenyl)- J = 7.2 Hz, 2H), 3.19-3.09 (m, 1H), 2.891-(spiro[3.3]heptan-2- (s, 2H), 2.84-2.70 (m, 3H), 2.64-2.53yl)methanesulfonamide (m, 1H), 2.21-2.12 (m, 2H), 2.08-1.94 (m, 3H),1.90-1.71 (m, 7H), 1.69-1.54 (m, 1H). 210 (S)-3-cyano-N-(2,3-difluoro-558.1 (400 MHz, DMSO- d₆) δ 8.42 (d, J = 5.1 Example4-((3-(2-(piperidin-3- Hz, 2H), 8.22 (dd, J = 4.8, 1.9 Hz, 1H), 46ylamino)pyrimidin-4- 7.43-7.35 (m, 1H), 7.35-7.26 (m, 2H),yl)pyridin-2-yl)oxy)phenyl)- 7.18-7.07 (m, 1H), 6.97-6.86 (m, 1H),3-methylbutane-1- 4.08 (s, 1H), 3.07 (d, J = 12.4 Hz, 1H), sulfonamide3.01-2.86 (m, 3H), 2.81-2.62 (m, 3H), 2.02-1.88 (m, 3H), 1.88-1.77 (m,1H), 1.66-1.40 (m, 2H), 1.31 (s, 6H). 211 (S)-N-(2,3-difluoro-4-((3-(2-569.1 (400 MHz, DMSO- d₆) δ 8.39 (d, J = 5.1 Example (piperidin-3- Hz,2H), 8.18 (dd, J = 4.9, 2.0 Hz, 1H), 46 ylamino)pyrimidin-4- 7.70-7.62(m, 2H), 7.36-7.22 (m, 3H), yl)pyridin-2-yl)oxy)phenyl)-4- 7.03-6.89 (m,3H), 6.90-6.76 (m, 1H), methoxybenzenesulfonamide 5.75 (s, 0H), 4.07 (s,1H), 3.78 (s, 3H), 3.17 (s, 0H), 3.11-3.01 (m, 1H), 2.81- 2.63 (m, 2H),2.54 (s, 0H), 2.07 (s, 0H), 1.99-1.91 (m, 1H), 1.87-1.77 (m, 1H),1.68-1.49 (m, 2H). 212 (S)-N-(2,3-difluoro-4-((3-(2- 569.1 (400 MHz,DMSO- d₆) δ 8.39 (d, J = 5.1 Example (piperidin-3- Hz, 2H), 8.18 (dd, J= 4.8, 2.0 Hz, 1H), 46 ylamino)pyrimidin-4- 7.44-7.17 (m, 7H), 7.07-6.88(m, 2H), yl)pyridin-2-yl)oxy)phenyl)- 6.84-6.68 (m, 1H), 4.11 (s, 1H),3.76 (s, 3-methoxybenzenesulfonamide 3H), 3.19-3.06 (m, 1H), 2.90-2.65(m, 2H), 2.11-1.75 (m, 2H), 1.73-1.51 (m, 2H). 213(S)-1-(4-chlorophenyl)-N- 587.1 (400 MHz, DMSO- d₆) δ 8.42 (d, J = 5.1Example (2,3-difluoro-4-((3-(2- Hz, 2H), 8.22 (dd, J = 4.8, 1.9 Hz, 1H),46 (piperidin-3- 7.45-7.26 (m, 8H), 7.24-7.09 (m, 1H),ylamino)pyrimidin-4- 7.05-6.83 (m, 1H), 4.17 (s, 2H), 4.08 (s,yl)pyridin-2- 1H), 3.11-3.00 (m, 1H), 2.80-2.61 (m,yl)oxy)phenyl)methanesulfonamide 2H), 2.06-1.93 (m, 1H), 1.91-1.77 (m,1H), 1.72-1.49 (m, 2H). 214 (S)-N-(2,3-difluoro-4-((3-(2- 540.1 (400MHz, DMSO- d₆) δ 8.84 (d, J = 2.2 Example (piperidin-3- Hz, 1H), 8.56(dd, J = 4.8, 1.7 Hz, 1H), 46 ylamino)pyrimidin-4- 8.40 (d, J = 5.1 Hz,2H), 8.27-8.13 (m, yl)pyridin-2- 1H), 8.11-7.97 (m, 1H), 7.50-7.34 (m,yl)oxy)phenyl)pyridine-3- 2H), 7.32-7.22 (m, 2H), 7.02-6.91 (m,sulfonamide 1H), 6.81-6.61 (m, 1H), 4.37-4.00 (m, 1H), 3.25-3.11 (m,4H), 2.93-2.71 (m, 2H), 2.05-1.83 (m, 2H), 1.75-1.45 (m, 2H). 215(S)-2-cyclohexyl-N-(2,3- 573.2 (400 MHz, DMSO- d₆) δ 8.39 (d, J = 5.1Example difluoro-4-((3-(2-(piperidin- Hz, 2H), 8.21 (dd, J = 4.8, 2.0Hz, 1H), 46 3-ylamino)pyrimidin-4- 7.40-7.13 (m, 4H), 7.13-7.00 (m, 1H),yl)pyridin-2- 4.03 (d, J = 43.3 Hz, 3H), 3.17 (s, 5H),yl)oxy)phenyl)ethane-1- 3.08-2.87 (m, 3H), 2.73-2.54 (m, 2H),sulfonamide 1.62 (ddt, J = 18.3, 6.7, 2.8 Hz, 8H), 1.16 (tdd, J = 10.5,7.2, 2.9 Hz, 3H), 0.86 (p, J = 10.3, 9.6 Hz, 3H). 216(S)-3-cyano-N-(2,3-difluoro- 558.1 (400 MHz, DMSO- d₆) δ 8.42 (d, J =5.1 Example 4-((3-(2-(piperidin-3- Hz, 1H), 8.33-8.12 (m, 1H), 7.47-7.2546 ylamino)pyrimidin-4- (m, 3H), 7.25-7.11 (m, 1H), 7.04-6.90yl)pyridin-2-yl)oxy)phenyl)- (m, 1H), 4.10 (s, 2H), 3.17 (s, 2H), 3.102,2-dimethylpropane-1- (d, J = 13.1 Hz, 1H), 3.02 (s, 2H), 2.78 (s,sulfonamide 2H), 2.75-2.64 (m, 1H), 2.05-1.93 (m, 1H), 1.90-1.81 (m,1H), 1.72-1.54 (m, 2H), 1.18 (s, 6H). 217 N-(2,3-difluoro-4-((3-(2-567.1 (400 MHz, DMSO- d₆) δ 8.41 (d, J = 5.1 Example (((S)-piperidin-3-Hz, 2H), 8.21 (dd, J = 4.8, 1.9 Hz, 1H), 46 yl)amino)pyrimidin-4-7.40-7.22 (m, 3H), 7.24-7.12 (m, 1H), yl)pyridin-2-yl)oxy)phenyl)-7.07-6.92 (m, 1H), 4.05 (s, 1H), 3.13- 2-(2,2- 2.98 (m, 3H), 2.78-2.62(m, 2H), 2.03- difluorocyclopropyl)ethane- 1.76 (m, 5H), 1.65-1.41 (m,2H), 1.25- 1-sulfonamide 1.11 (m, 1H). (MD) 218(S)-N-(2,3-difluoro-4-((3-(2- 539.1 (400 MHz, DMSO- d₆) δ 8.39 (d, J =5.1 Example (piperidin-3- Hz, 2H), 8.18 (dd, J = 4.8, 2.0 Hz, 1H), 46ylamino)pyrimidin-4- 7.81-7.62 (m, 2H), 7.52-7.32 (m, 4H), yl)pyridin-2-7.33-7.22 (m, 2H), 6.99-6.87 (m, 1H), yl)oxy)phenyl)benzenesulfonamide6.83-6.66 (m, 1H), 5.75 (s, 1H), 4.23- 3.98 (m, 1H), 3.17 (s, 1H),3.16-3.04 (m, 1H), 2.87-2.62 (m, 2H), 2.05-1.88 (m, 1H), 1.91-1.73 (m,1H), 1.72-1.51 (m, 2H). 219 (S)-4-cyano-N-(2,3-difluoro- 564.1 (400 MHz,DMSO-d₆) δ 8.41 (d, J = 5.1 Example 4-((3-(2-(piperidin-3- Hz, 1H), 8.18(dd, J = 4.8, 1.9 Hz, 1H), 46 ylamino)pyrimidin-4- 7.85 (s, 4H), 7.42(d, J = 7.3 Hz, 1H), yl)pyridin-2- 7.36-7.14 (m, 2H), 7.01-6.86 (m, 1H),yl)oxy)phenyl)benzenesulfonamide 6.79-6.61 (m, 1H), 4.16 (s, 1H), 3.39(t, J = 5.9 Hz, 2H), 3.24-3.09 (m, 1H), 2.96-2.70 (m, 2H), 1.97 (d, J =12.1 Hz, 1H), 1.93-1.85 (m, 1H), 1.77-1.49 (m, 2H). 220(S)-3-cyano-N-(2,3-difluoro- 564.1 (400 MHz, DMSO- d₆) δ 8.41 (d, J =5.1 Example 4-((3-(2-(piperidin-3- Hz, 1H), 8.18 (dd, J = 4.8, 2.0 Hz,1H), 46 ylamino)pyrimidin-4- 8.11-7.91 (m, 2H), 7.94-7.81 (m, 1H),yl)pyridin-2- 7.73-7.54 (m, 1H), 7.42 (d, J = 7.4 Hz,yl)oxy)phenyl)benzenesulfonamide 1H), 7.34-7.16 (m, 2H), 7.01-6.83 (m,1H), 6.81-6.63 (m, 1H), 4.16 (s, 1H), 3.25-3.09 (m, 1H), 2.97-2.71 (m,2H), 2.08-1.83 (m, 2H), 1.63 (tt, J = 20.8, 10.2 Hz, 1H). 221(S)-N-(2,3-difluoro-4-((3-(2- 543.1 (400 MHz, DMSO- d₆) δ 8.38 (d, J =5.1 Example (piperidin-3- Hz, 2H), 8.19 (dd, J = 4.8, 1.9 Hz, 1H), 46ylamino)pyrimidin-4- 7.65 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 1.4yl)pyridin-2-yl)oxy)phenyl)- Hz, 1H), 7.38-7.21 (m, 3H), 7.16 (td, J =1-methyl-1H-imidazole-4- 8.9, 2.2 Hz, 1H), 6.91 (td, J = 8.7, 2.0 Hz,sulfonamide 1H), 4.00 (s, 1H), 3.65 (s, 3H), 3.09- 2.93 (m, 1H),2.79-2.57 (m, 2H), 1.94 (d, J = 6.7 Hz, 1H), 1.83-1.74 (m, 1H),1.62-1.45 (m, 2H). 222 (S)-N-(2,3-difluoro-4-((3-(2- 543.1 (400 MHz,DMSO- d₆) δ 8.40 (d, J = 5.1 Example (piperidin-3- Hz, 1H), 8.19 (dd, J= 4.8, 1.9 Hz, 1H), 46 ylamino)pyrimidin-4- 7.97 (s, 1H), 7.53 (s, 1H),7.40-7.17 (m, yl)pyridin-2-yl)oxy)phenyl)- 3H), 7.15-6.93 (m, 1H),6.94-6.69 (m, 1-methyl-1H-pyrazole-4- 1H), 4.07 (s, 1H), 3.80 (s, 3H),3.14- sulfonamide 3.03 (m, 1H), 2.79-2.60 (m, 2H), 2.04- 1.88 (m, 1H),1.88-1.76 (m, 1H), 1.71- 1.48 (m, 2H). 223 (S)-N-(2,3-difluoro-4-((3-(2-623.1 (400 MHz, DMSO-d₆) δ 8.41 (d, J = 5.1 Example (piperidin-3- Hz,1H), 8.19 (dd, J = 4.9, 2.0 Hz, 1H), 46 ylamino)pyrimidin-4- 7.87-7.78(m, 2H), 7.45 (d, J = 7.3 Hz, yl)pyridin-2-yl)oxy)phenyl)-4- 1H),7.42-7.35 (m, 2H), 7.32-7.23 (m, (trifluoromethoxy)benzenesulfonamide2H), 6.97-6.87 (m, 1H), 6.77-6.67 (m, 1H), 4.17-4.08 (m, 1H), 3.17 (d, J= 4.9 Hz, 2H), 2.88-2.71 (m, 2H), 2.01-1.93 (m, 1H), 1.93-1.83 (m, 1H),1.76-1.50 (m, 2H). 224 (S)-N-(2,3-difluoro-4-((3-(2- 569.1 (400 MHz,DMSO-d₆) δ 8.49-8.28 (m, Example (piperidin-3- 2H), 8.18 (dd, 1H), 7.72(dd, J = 7.8, 1.8 46 ylamino)pyrimidin-4- Hz, 1H), 7.54-7.45 (m, 1H),7.34-7.21 yl)pyridin-2-yl)oxy)phenyl)-2- (m, 3H), 7.14 (d, J = 8.1 Hz,1H), 7.06- methoxybenzenesulfonamide 6.88 (m, 3H), 3.99 (s, 1H), 3.81(s, 3H), 3.02-2.92 (m, 1H), 2.67-2.52 (m, 2H), 1.98-1.88 (m, 1H),1.81-1.71 (m, 1H), 1.60-1.46 (m, 2H), −4.10 (s, 1H). 225(S)-1-(3-chlorophenyl)-N- 587.1 (400 MHz, DMSO- d₆) δ 8.42 (d, J = 5.1Example (2,3-difluoro-4-((3-(2- Hz, 2H), 8.22 (dd, J = 4.8, 1.9 Hz, 1H),46 (piperidin-3- 7.48-7.24 (m, 8H), 7.21-7.12 (m, 1H),ylamino)pyrimidin-4- 6.99-6.80 (m, 1H), 4.17 (s, 2H), 4.09 (s,yl)pyridin-2- 1H), 3.14-3.02 (m, 1H), 2.84-2.60 (m,yl)oxy)phenyl)methanesulfonamide 2H), 2.11-1.92 (m, 1H), 1.90-1.78 (m,1H), 1.73-1.51 (m, 2H). 226 (S)-N-(2,3-difluoro-4-((3-(2- 547.2 (400MHz, DMSO- d₆) δ 8.39 (d, J = 5.1 Example (piperidin-3- Hz, 2H), 8.21(dd, J = 4.8, 2.0 Hz, 1H), 46 ylamino)pyrimidin-4- 7.44-7.12 (m, 4H),7.11-6.97 (m, 1H), yl)pyridin-2-yl)oxy)phenyl)- 3.98 (s, 1H, 3.17 (s,1H), 3.06-2.81 (m, 3,3-dimethylbutane-1- 3H), 2.66-2.54 (m, 1H),2.04-1.86 (m, sulfonamide 1H), 1.77-1.69 (m, 1H), 1.67-1.43 (m, 4H),0.87 (s, 10H). 227 (S)-2-chloro-N-(2,3-difluoro- 587.1 (400 MHz, DMSO-d₆) δ 8.47-8.30 (m, Example 4-((3-(2-(piperidin-3- 2H), 8.22 (dd, J =4.8, 2.0 Hz, 1H), 7.56- 46 ylamino)pyrimidin-4- 7.47 (m, 1H), 7.46-7.38(m, 1H), 7.36 yl)pyridin-2- (d, J = 7.5 Hz, 1H), 7.33-7.25 (m, 4H),yl)oxy)phenyl)benzenesulfonamide 7.21 (td, 1H), 6.89 (t, J = 8.9, 2.0Hz, 1H), 4.31 (s, 2H), 4.10 (s, 1H), 3.09 (d, J = 12.7 Hz, 1H),2.80-2.65 (m, 2H), 2.01- 1.93 (m, 1H), 1.89-1.80 (m, 1H), 1.67- 1.51 (m,2H). 228 (S)-1-cyclopentyl-N-(2,3- 545.3 (400 MHz, DMSO- d₆) δ 8.51-8.32(m, Example difluoro-4-((3-(2-(piperidin- 1H), 8.22 (dd, J = 4.8, 2.0Hz, 1H), 7.33 46 3-ylamino)pyrimidin-4- (dd, J = 7.6, 4.9 Hz, 1H),7.29-7.16 (m, yl)pyridin-2- 3H), 7.07 (t, J = 8.7, 2.0 Hz, 1H), 3.98 (s,yl)oxy)phenyl)methanesulfonamide 1H), 3.06 (d, J = 6.8 Hz, 2H),3.00-2.90 (m, 1H), 2.67-2.52 (m, 2H), 2.31-2.18 (m, 1H), 2.00-1.80 (m,3H), 1.80-1.66 (m, 1H), 1.65-1.41 (m, 5H), 1.33-1.19 (m, 2H). 229(S)-1-(3-cyanophenyl)-N- 578.2 (400 MHz, DMSO-d₆) δ 8.43 (d, J = 5.1Example (2,3-difluoro-4-((3-(2- Hz, 2H), 8.23 (dd, J = 4.8, 2.0 Hz, 1H),46 (piperidin-3- 7.78-7.69 (m, 2H), 7.65 (d, J = 7.8, 1.5ylamino)pyrimidin-4- Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.38 (d,yl)pyridin-2- J = 7.5 Hz, 1H), 7.35-7.22 (m, 2H), 7.17yl)oxy)phenyl)methanesulfonamide (t, J = 9.0, 2.2 Hz, 1H), 6.88 (t, J =8.9, 2.0 Hz, 1H), 4.21 (s, 2H), 4.12 (s, 1H), 3.11 (d, J = 12.7 Hz, 1H),2.83-2.65 (m, 2H), 2.01-1.93 (m, 1H), 1.91-1.81 (m, 1H), 1.72-1.52 (m,2H). 230 (S)-N-(2,3-difluoro-4-((3-(2- 561.3 (400 MHz, DMSO- d₆) δ8.50-8.32 (m, Example (piperidin-3- 1H), 8.21 (dd, J = 4.9, 1.9 Hz, 1H),7.33 46 ylamino)pyrimidin-4- (dd, J = 7.5, 4.8 Hz, 1H), 7.28-7.13 (m,yl)pyridin-2-yl)oxy)phenyl)- 3H), 7.04 (t, J = 8.8, 2.0 Hz, 1H), 3.96(s, 4,4-dimethylpentane-1- 1H), 3.20-3.16 (m, 1H), 2.98-2.90 (m,sulfonamide 3H), 2.64-2.52 (m, 1H), 2.00-1.88 (m, 1H), 1.79-1.61 (m,3H), 1.59-1.47 (m, 2H), 1.28-1.19 (m, 2H), 0.87 (s, 9H). 231(S)-N-(2,3-difluoro-4-((3-(2- 571.2 (400 MHz, DMSO- d₆) δ 8.42 (d, J =5.2 Example (piperidin-3- Hz, 2H), 8.23 (dd, J = 4.8, 2.0 Hz, 1H), 46ylamino)pyrimidin-4- 8.19 (s, 1H), 7.39-7.27 (m, 4H), 7.21-yl)pyridin-2-yl)oxy)phenyl)-1-(3- 7.05 (m, 4H), 6.91 (td, J = 8.9, 2.0Hz, fluorophenyl)methanesulfonamide 1H), 4.20 (s, 2H), 4.10 (s, 1H),3.06 (s, 1H), 2.72 (td, J = 13.3, 11.8, 6.6 Hz, 2H), 2.00-1.93 (m, 1H),1.87-1.79 (m, 1H), 1.60 (q, J = 12.4, 11.3 Hz, 2H). 232(S)-N-(2,3-difluoro-4-(3-(2- 567.2 (400 MHz, DMSO-d₆) δ 8.48-8.32 (m,Example (piperidin-3- 2H), 8.21 (dd, J = 4.9, 1.9 Hz, 1H), 7.35- 46ylamino)pyrimidin-4- 7.25 (m, 3H), 7.20-7.11 (m, 1H), 6.98-yl)pyridin-2-yloxy)phenyl)-1-(3,3- 6.89 (m, 1H), 4.11-3.99 (m, 1H), 3.12difluorocyclobutyl)methanesulfonamide (d, J = 6.8 Hz, 2H), 3.06-2.99 (m,1H), 2.75-2.60 (m, 4H), 2.48-2.36 (m, 2H), 1.99-1.91 (m, 1H), 1.84-1.73(m, 1H), 1.66-1.49 (m, 2H). 233 (S)-N-(2,3-difluoro-4-(3-(2- 554.2 (400MHz, DMSO-d₆) δ 8.66-8.57 (m, Example (piperidin-3- 2H), 8.46 (dd, J =7.5, 2.0 Hz, 1H), 8.43 46 ylamino)pyrimidin-4- (d, J = 5.2 Hz, 1H), 8.23(dd, J = 4.8, 1.9 yl)pyridin-2-yloxy)phenyl)- Hz, 1H), 7.97-7.91 (m,1H), 7.50 (dd, J = 1-(pyridin-3- 7.9, 4.9 Hz, 1H), 7.35 (dd, J = 7.6,4.9 yl)methanesulfonamide Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.25- 7.12(m, 2H), 4.65 (s, 2H), 4.30-4.21 (m, 1H), 3.41 (dd, J = 12.1, 4.1 Hz,1H), 3.23-3.20 (m, 1H), 2.95-2.84 (m, 2H), 2.05-1.89 (m, 2H), 1.82-1.61(m, 2H). ¹H NMR taken at 360K 234 (S)-N-(2,3-difluoro-4-(3-(2- 554.2(400 MHz, DMSO-d₆) δ 8.58-8.55 (m, Example (piperidin-3- 2H), 8.47 (dd,J = 7.7, 1.9 Hz, 1H), 8.42 46 ylamino)pyrimidin-4- (d, J = 5.1 Hz, 1H),8.23 (dd, J = 4.9, 1.9 yl)pyridin-2-yloxy)phenyl)- Hz, 1H), 7.44-7.40(m, 2H), 7.35 (dd, J = 1-(pyridin-4- 7.5, 4.8 Hz, 1H), 7.30 (d, J = 5.2Hz, yl)methanesulfonamide 1H), 7.24-7.12 (m, 2H), 4.60 (s, 2H),4.32-4.22 (m, 1H), 3.40 (dd, J = 11.9, 4.2 Hz, 1H), 3.20-3.12 (m, 1H),2.93- 2.84 (m, 2H), 2.04-1.88 (m, 2H), 1.84- 1.60 (m, 2H). ¹H NMR takenat 360K 235 (S)-N-(2,3-difluoro-4-(3-(2- 571.2 (400 MHz, DMSO-d₆) δ8.51-8.32 (m, Example (piperidin-3- 2H), 8.22 (dd, J = 4.8, 2.0 Hz, 1H),7.40- 46 ylamino)pyrimidin-4- 7.26 (m, 5H), 7.19-7.08 (m, 3H), 6.94-yl)pyridin-2-yloxy)phenyl)-1-(4- 6.86 (m, 1H), 4.17 (s, 2H), 4.07-4.02fluorophenyl)methanesulfonamide (m, 1H), 3.46-3.38 (m, 1H), 3.24-3.16(m, 1H), 3.07-2.98 (m, 1H), 2.74-2.60 (m, 1H), 1.99-1.92 (m, 1H),1.84-1.74 (m, 1H), 1.63-1.52 (m, 2H). 236 (S)-1-(1-methyl-1H-pyrazol-575.2 (400 MHz, DMSO-d₆) δ 8.51-8.32 (m, Example3-yl)-N-(2,3,6-trifluoro-4-(3- 2H), 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 7.5530 (2-(piperidin-3- (d, J = 2.2 Hz, 1H), 7.37-7.30 (m, 2H),ylamino)pyrimidin-4- 7.28 (d, J = 5.1 Hz, 1H), 7.15-7.07 (m,yl)pyridin-2- 1H), 6.27 (d, J = 2.1 Hz, 1H), 4.12-3.96yloxy)phenyl)methanesulfonamide (m, 3H), 3.78 (s, 3H), 3.06-2.99 (m,1H), 2.74-2.59 (m, 2H), 1.99-1.92 (m, 1H), 1.84-1.76 (m, 1H), 1.65-1.50(m, 2H). 237 N-[2-fluoro-3-methyl-4-[[3- 549.1 (400 MHz, DMSO-d₆) δ8.49-8.32 (m, Example [2-[[(3S)-3- 3H), 8.22-8.16 (m, 1H), 7.44-7.10 (m,47 piperidyl]amino]pyrimidin- 8H), 6.88 (dd, J = 8.8, 1.6 Hz, 1H), 4.404-yl]-2-pyridyl]oxy]phenyl]- (s, 2H), 3.91-3.87 (m, 1H), 3.15-3.08 1phenylmethanesulfonamide (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.41 (m, 1H),2.00 (s, 3H), 1.94-1.88 (m, 1H), 1.70-1.63 (m, 1H), 1.56-1.36 (m, 2H),1.26-1.13 (m, 1H). 238 (S)-N-(2,3-difluoro-4-(3-(2- 554.2 (400 MHz,DMSO-d₆) δ 8.52-8.47 (m, Example (piperidin-3- 1H), 8.42-8.34 (m, 2H),8.21 (dd, J = 18 ylamino)pyrimidin-4- 4.9, 2.1 Hz, 1H), 7.78-7.70 (m,1H), yl)pyridin-2-yloxy)phenyl)- 7.52 (d, J = 7.8 Hz, 1H), 7.32-7.18 (m,1-(pyridin-2- 4H), 7.01-6.92 (m, 1H), 6.84 (d, J = 7.8yl)methanesulfonamide Hz, 1H), 4.47 (s, 2H), 4.04-3.94 (m, 1H),3.21-3.19 (m, 1H), 2.93-2.88 (m, 1H), 2.89 (d, J = 3.8 Hz, 1H),2.68-2.57 (m, 2H), 2.00-1.89 (m, 1H), 1.78-1.69 (m, 1H), 1.62-1.47 (m,2H). ¹H NMR taken at 360K 248 1-(2,3-difluoro-4-((3-(2- 495.2 (400 MHz,CD₃OD) δ 8.55 (d, J = 7.9 Hz, Example (((S)-piperidin-3- 1H), 8.38 (d, J= 5.3 Hz, 1H), 8.22-8.12 48 yl)amino)pyrimidin-4- (m, 1H), 7.38 (d, J =5.3 Hz, 1H), 7.35- yl)pyridin-2-yl)oxy)phenyl)- 7.25 (m, 2H), 7.23-7.14(m, 1H), 4.14 3-ethylpyrrolidin-2-one (s, 1H), 3.94-3.77 (m, 2H), 3.41(d, J = 13.6 Hz, 1H), 3.10 (d, J = 12.4 Hz, 1H), 2.83-2.58 (m, 3H),2.52-2.39 (m, 1H), 2.13 (s, 1H), 2.07-1.88 (m, 3H), 1.81- 1.49 (m, 3H),1.08 (t, J = 7.4 Hz, 3H) 249 1-(2,3-difluoro-4-((3-(2- 495.2 (400 MHz,CD₃OD) δ 8.55 (d, J = 7.9 Hz, Example (((S)-piperidin-3- 1H), 8.38 (d, J= 5.3 Hz, 1H), 8.22-8.12 48 yl)amino)pyrimidin-4- (m, 1H), 7.38 (d, J =5.3 Hz, 1H), 7.35- yl)pyridin-2-yl)oxy)phenyl)- 7.25 (m, 2H), 7.23-7.14(m, 1H), 4.14 3-ethylpyrrolidin-2-one (s, 1H), 3.94-3.77 (m, 2H), 3.41(d, J = 13.6 Hz, 1H), 3.10 (d, J = 12.4 Hz, 1H), 2.83-2.58 (m, 3H),2.52-2.39 (m, 1H), 2.13 (s, 1H), 2.07-1.88 (m, 3H), 1.81- 1.49 (m, 3H),1.08 (t, J = 7.4 Hz, 3H) 250 (S)-1-(4-cyanophcnyl)-N- 578.2 (400 MHz,DMSO-d₆) δ 8.71-8.3 (m, Example (2,3-difluoro-4-((3-(2- 3H), 8.24 (d, J= 6.4 Hz, 1H), 7.83 (d, J = 27 (piperidin-3- 8.0 Hz, 2H), 7.57 (d, J =8.0 Hz, 2H), ylamino)pyrimidin-4- 7.47-7.53(m, 1H), 7.37-7.32 (m, 2H),yl)pyridin-2- 7.23-7.18 (m, 1H), 7.11-7.06 (m, 1H),yl)oxy)phenyl)methanesulfonamide 4.54 (s, 2H), 4.22-4.11 (m, 1H), 3.43-3.40 (m, 1H), 3.32-3.31 (m, 1H), 3.21- 3.17 (m, 1H), 2.88-2.78 (m, 2H),2.07- 1.88 (m, 2H), 1.72-1.59 (m, 2H) 251 1-(3,3-difluorocyclobutyl)-617.2 (300 MHz, CD₃OD) δ 8.54 (d, J = 7.2 Hz, ExampleN-(2,3,6-trifluoro-4-((3-(2- 1H), 8.36 (d, J = 5.1 Hz, 1H), 8.22-8.16 42(((3S,5S)-5-fluoro-5- (m, 1H), 7.37-7.27 (m, 2H), 7.19-7.08methylpiperidin-3- (m, 1H), 4.46-4.28 (m, 1H), 3.48-3.34yl)amino)pyrimidin-4- (m, 3H), 3.12-3.01 (m, 1H), 2.93-2.35yl)pyridin-2- (m, 8H), 1.87-1.53 (m, 1H), 1.40-1.33yl)oxy)phenyl)methanesulfonamide (m, 3H) 252 2-methoxy-N-(2,3,6- 557.1(400 MHz, CD₃OD) δ 8.56 (d, J = 7.6 Hz, Exampletrifluoro-4-((3-(2-(((3S,5S)- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.19 (d, J= 40 5-fluoropiperidin-3- 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.15 (d,yl)amino)pyrimidin-4- J = 10.2, 1H), 4.99 (s, 1H), 4.42 (s, 1H),yl)pyridin-2- 3.94-3.86 (m, 2H), 3.67-3.48 (m, 2H),yl)oxy)phenyl)ethane-1- 3.39 (s, 3H), 3.31-3.26 (m, 1H), 3.23-3.17 (m,1H), sulfonamide 2.91-2.78 (m, 1H), 2.61-2.52 (m, 1H), 2.49-2.33 (m,1H), 1.91-1.78 (m, 1H) 253 3,3-difluoro-N-(2,3,6- 591.2 (400 MHz, CD₃OD)δ 8.56 (d, J = 7.5 Hz, Example trifluoro-4-((3-(2-(((3S,5S)- 1H), 8.37(d, J = 5.2 Hz, 1H), 8.20 (dd, J = 40 5-fluoropiperidin-3- 4.9, 1.9 Hz,1H), 7.37-7.30 (m, 2H), yl)amino)pyrimidin-4- 7.18-7.10 (m, 1H), 4.99(s, 1H), 4.42 (s, yl)pyridin-2- 1H), 3.40-3.35 (m, 3H), 3.21 (t, J =12.9 yl)oxy)phenyl)butane-1- Hz, 1H), 2.87 (dd, J = 37.1, 14.2 Hz, 1H),sulfonamide 2.62-2.39 (m, 4H), 1.89-1.64 (m, 4H) 254N-(2,3,6-trifluoro-4-((3-(2- 658.1 (400 MHz, CD₃OD) δ 8.83 (d, J = 2.0Hz, Example (((3S,5S)-5-fluoropiperidin- 1H), 8.56 (d, J = 7.5 Hz, 1H),8.39 (d, J = 40 3-yl)amino)pyrimidin-4- 5.3 Hz, 1H), 8.23-8.15 (m, 2H),7.86 (d, yl)pyridin-2-yl)oxy)phenyl)-1-(6- J = 8.0 Hz, 1H), 7.38 (d, J =5.2 Hz, 1H), (trifluoromethyl)pyridin-3- 7.33 (m, 1H), 7.14-7.04 (m,1H), 5.08- yl)methanesulfonamide 4.91 (m, 1H), 4.62 (s, 2H), 4.47 (s,1H), 3.44 (d, J = 11.8 Hz, 1H), 3.27 (d, J = 12.1 Hz, 1H), 2.94 (m, 1H),2.64 (t, J = 11.5 Hz, 1H), 2.50-2.38 (s, 1H), 1.96- 1.80 (m, 1H). 2551-(4-cyanophenyl)-N-(2,3,6- 628.2 (300 MHz, DMSO-d₆) δ 8.48-8.36 (m,Example trifluoro-4-((3-(2-(((3S,5S)- 2H), 8.28 (dd, J = 4.8, 1.9 Hz,1H), 7.95- 54 5-fluoropiperidin-3- 7.86 (m, 2H), 7.68 (d, J = 8.2 Hz,2H), yl)amino)pyrimidin-4- 7.60 (dd, J = 9.5, 6.2 Hz, 1H), 7.43 (dd, J =yl)pyridin-2-yl)oxy)-5- 7.6, 4.9 Hz, 1H), 7.24 (dd, J = 10.3, 6.6methylphenyl)methanesulfonamide Hz, 2H), 4.91-4.65 (m, 3H), 4.13 (s,1H), 3.25 (s, 3H), 3.05 (d, J = 13.0 Hz, 1H), 2.91 (t, J = 13.4 Hz, 1H),2.68 (dd, J = 34.3, 13.9 Hz, 1H), 2.48-2.35 (m, 1H), 2.15 (s, 1H), 1.81(dt, J = 38.7, 12.0 Hz, 1H) 256 1-(pyridin-3-yl)-N-(2,3,6- 590.1 (400MHz, CD₃OD) δ 8.67 (s, 1H), 8.55- Example trifluoro-4-((3-(2-(((3S,5S)-8.51 (m, 2H), 8.36 (d, J = 2.6 Hz, 1H), 40 5-fluoropiperidin-3-8.20-8.18 (m, 1H), 8.01 (d, J = 4.0 Hz, yl)amino)pyrimidin-4- 1H),7.48-7.47 (m, 1H), 7.40-7.29 (m, yl)pyridin-2- 2H), 7.14 (t, J = 3.6 Hz,1H), 4.99-4.89 yl)oxy)phenyl)methanesulfonamide (m, 1H), 4.54 (s, 2H),4.44 (s, 1H), 3.38- 3.35 (m, 1H), 3.22-3.13 (m, 1H), 2.93- 2.80 (m, 1H),2.65-2.60 (m, 1H), 2.55- 2.41 (m, 1H), 1.93-1.79 (m, 1H) 2571-phenyl-N-(2,3,6-trifluoro- 585.2 (400 MHz, CD₃OD) δ 8.53 (d, J = 6.4Hz, Example 4-((3-(2-(((3S,6S)-6- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.19(d, J = 56 methylpiperidin-3- 6.4 Hz, 1H), 7.50-7.48 (m, 2H), 7.38-7.29(m, 5H), yl)amino)pyrimidin-4- 7.04-6.99 (m, 1H), 4.40 yl)pyridin-2- (s,2H), 4.13-4.02 (m, 1H), 3.54-3.50 yl)oxy)phenyl)methanesulfonamide (m,1H), 3.00-2.85 (m, 1H), 2.66-2.60 (m, 1H), 2.19-2.16 (m, 1H), 1.97-1.93(m, 1H),1.64-1.45 (m, 2H), 1.24 (d, J = 4.8 Hz, 3H) 258N-(2,3,6-trifluoro-4-((3-(2- 568.1 (400 MHz, CD₃OD) δ 8.56 (d, J = 7.2Hz, Example (((3S,5S)-5-fluoropiperidin- 1H), 8.36 (d, J = 5.2 Hz, 1H),8.20 (dd, J = 54 3-yl)amino)pyrimidin-4- 4.8, 2.0 Hz, 1H), 7.37-7.29 (m,2H), yl)pyridin-2- 7.18-7.09 (m, 1H), 4.82 (s, 1H), 4.38 (s,yl)oxy)phenyl)pyrrolidine-1- 1H), 3.42-3.34 (m, 4H), 3.29-3.18 (m,sulfonamide 1H), 3.14 (t, J = 12.8 Hz, 1H), 2.88- 2.71(m, 1H), 2.58-2.48(m, 1H), 2.40 (s, 1H), 2.03-1.92 (m, 4H), 1.95-1.73 (m, 1H). 2591-phenyl-N-(2,3,6-trifluoro- 589.2 (400 MHz, CD₃OD) δ 8.54 (d, J = 7.6Hz, Example 4-((3-(2-(((3S,5R)-5- 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.22(dd, J = 40 fluoropiperidin-3- 4.9, 1.9 Hz, 1H), 7.50-7.48 (m, 2H),yl)amino)pyrimidin-4- 7.41-7.31 (m, 5H), 7.17 (t, J = 7.4 Hz,yl)pyridin-2- 1H), 4.71 (d, J = 48.7 Hz, 1H), 4.53 (s,yl)oxy)phenyl)methanesulfonamide 2H), 4.18 (s, 1H), 3.17-3.16 (m, 2H),2.81-2.67 (m, 2H), 2.41-2.34 (m, 1H), 1.89 (s, 1H) 2602,2,2-trifluoro-N-(2,3,6- 581.8 (400 MHz, CD₃OD) δ 8.74 (s, 1H), 8.51Example trifluoro-4-((3-(2-(((3S,5S)- (t, J = 8.5 Hz, 1H), 8.36 (s, 1H),7.86- 40 5-fluoropiperidin-3- 7.85 (m, 1H), 7.43-7.42 (m, 1H), 7.31-yl)amino)pyrimidin-4- 7.29 (m, 1H), 5.31 (d, J = 44.7 Hz, 1H),yl)pyridin-2- 4.90-4.80 (s, 1H), 4.35 (q, J = 9.3 Hz,yl)oxy)phenyl)ethane-1- 2H), 3.78-3.64 (m, 2H), 3.50-3.40 (m,sulfonamide hydrochloride 1H), 3.10 (s, 1H), 2.63 (s, 1H), 2.20- 2.10(m, 1H) 261 1-(1-fluorocyclopropyl)-N- 571.1 (400 MHz, CD₃OD) δ 8.57 (d,J = 7.3 Hz, Example (2,3,6-trifluoro-4-((3-(2- 1H), 8.37 (d, J = 5.3 Hz,1H), 8.20 (dd, J = 40 (((3S,5S)-5-fluoropiperidin- 4.8, 1.9 Hz, 1H),7.38-7.30 (m, 2H), 3-yl)amino)pyrimidin-4- 7.17-7.11 (m, 1H), 5.00-4.80(m, 1H), yl)pyridin-2- 4.42 (s, 1H), 3.80 (s, 1H), 3.74 (d, J =yl)oxy)phenyl)methanesulfonamide 20.4 Hz, 1H), 3.36-3.31 (m, 1H), 3.21(t, J = 12.8 Hz, 1H), 2.87 (dd, J = 37.0, 14.2 Hz, 1H), 2.62-2.53 (m,1H), 2.43 (s, 1H), 1.95-1.75 (m, 1H), 1.25-1.15 (m, 2H), 1.04-0.96 (m,2H) 262 1-phenyl-N-(2,3,6-trifluoro- 603.2 (400 MHz, CD₃OD) δ 8.54 (d, J= 7.6 Hz, Example 4-((3-(2-(((3S,5R)-5- 1H), 8.36 (d, J = 5.2 Hz, 1H),8.20 (dd, J = 61 (fluoromethyl)piperidin-3- 4.9, 1.9 Hz, 1H), 7.50 (dd,J = 7.7, 1.8 yl)amino)pyrimidin-4- Hz, 2H), 7.42-7.35 (m, 1H), 7.39-7.27yl)pyridin-2- (m, 4H), 7.09 (ddd, J = 9.8, 6.6, 2.2 Hz,yl)oxy)phenyl)methanesulfonamide 1H), 4.49-4.33 (m, 3H), 4.37-4.21 (m,1H), 4.16 (s, 1H), 3.44 (dd, J = 12.1, 4.3 Hz, 1H), 3.20 (d, J = 11.9Hz, 1H), 2.49 (d, J = 11.8 Hz, 1H), 2.43 (d, J = 11.1 Hz, 1H), 2.15 (t,J = 14.8 Hz, 2H), 1.35 (q, J = 12.4 Hz, 1H) 263N-(2,3,6-trifluoro-4-((3-(2- 582.2 (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.37Example (((3S,5S)-5-fluoropiperidin- (d, J = 5.2 Hz, 1H), 8.21 (dd, J =4.8, 2.0 57 3-yl)amino)pyrimidin-4- Hz, 1H), 7.34 (dd, J = 7.6, 4.8 Hz,2H), yl)pyridin-2- 7.19-7.09 (m, 1H), 4.83 (s, 1H), 4.39 (s,yl)oxy)phenyl)piperidine-1- 1H), 3.27 (t, J = 5.2 Hz, 5H), 3.15 (t, J =sulfonamide 13.2 Hz, 1H), 2.88-2.69 (m, 1H), 2.58- 2.48 (m, 1H), 2.41(s, 1H), 1.83 (dt, J = 40.0, 12.0 Hz, 1H), 1.66 (d, J = 5.6 Hz, 4H),1.60 (d, J = 4.8 Hz, 2H) 264 1-(2,2-difluorocyclobutyl)- 603.1 (300 MHz,CD₃OD) δ 8.57 (d, J = 7.5 Hz, Example N-(2,3,6-trifluoro-4-((3-(2- 1H),8.38 (d, J = 5.3 Hz, 1H), 8.31-8.20 40 (((3S,5S)-5-fluoropiperidin- (m,1H), 7.41-7.26 (m, 2H), 7.15 (t, J = 3-yl)amino)pyrimidin-4- 8.9 Hz,1H), 5.10-4.86 (m, 2H), 4.42 (s, yl)pyridin-2- 1H), 3.58-3.48 (m, 1H),3.40-3.37 (m, yl)oxy)phenyl)methanesulfonamide 2H), 3.21 (t, J = 12.9Hz, 1H), 2.95-2.86 (m, 1H), 2.70-2.41 (m, 4H), 2.19 (s, 1H), 1.96-1.64(m, 2H) 265 1-(2,2-difluorocyclobutyl)- 603.2 (300 MHz, CD₃OD) δ 8.57(d, J = 7.7 Hz, Example N-(2,3,6-trifluoro-4-((3-(2- 1H), 8.38 (d, J =5.3 Hz, 1H), 8.25-8.14 40 (((3S,5S)-5-fluoropiperidin- (m, 1H),7.40-7.30 (m, 2H), 7.22-7.08 3-yl)amino)pyrimidin-4- (m, 1H), 5.05-4.80(m, 2H) 4.42 (s, 1H), yl)pyridin-2- 3.59-3.23 (m, 4H), 2.99-2.74 (m,1H), yl)oxy)phenyl)methanesulfonamide 2.70-2.37 (m, 4H), 2.19 (s, 1H),2.00- 1.62 (m, 2H) 266 4-(2-(4- 542.1 (300 MHz, CD₃OD) δ 8.55 (d, J =7.2 Hz, Example (dimethylsulfamoylamino)- 1H), 8.34 (d, J = 5.2 Hz, 1H),8.18 (m, 64 2,3,5-trifluoro-phenoxy)-3- 1H), 7.38-7.26 (m, 2H),7.20-7.02 (m, pyridyl)-2-(((3S,5S)-5- 1H), 4.93-4.79 (m, 1H), 4.36 (s,fluoro-3- 1H), 3.34-3.33(m, 1H), 3.13 (t, J = 13.6piperidyl)amino)pyrimidine Hz, 1H), 2.86 (s, 6H), 2.81-2.71 (m, 1H),2.60-2.45 (m, 1H), 2.39 (s, 1H), 1.96-1.66 (m, 1H) 2672-cyclopropyl-N-(2,3,6- 567.2 (300 MHz, CD₃OD) δ 8.54-8.51 (m, Exampletrifluoro-4-((3-(2-(((3S,5S)- 1H), 8.35 (d, J = 5.1 Hz, 1H), 8.18 (d, J= 40 5-fluoropiperidin-3- 5.1 Hz, 1H), 7.34-7.30 (m, 2H), 7.18-yl)amino)pyrimidin-4- 7.12 (m, 1H), 5.00-4.88 (m, 2H), 4.80-yl)pyridin-2- 4.75 (m, 1H), 4.42-4.31 (m, 1H), 3.20-yl)oxy)phenyl)ethane-1- 3.02 (m, 2H), 2.88-2.71 (m, 1H), 2.55-sulfonamide 2.31 (m, 2H), 1.88-1.76 (m, 3H), 0.89- 0.85 (m, 1H),0.55-0.49 (m, 2H), 0.18- 0.13 (m, 2H) 268 2,2-difluoro-N-(2,3,6- 609.2(400 MHz, CD₃OD) δ 8.54 (d, J = 6.1 Hz, Exampletrifluoro-4-((5-fluoro-3-(2- 2H), 8.27 (s, 1H), 7.83 (s, 1H), 7.29 (t, J= 40 (((3S,5S)-5-fluoropiperidin- 7.7 Hz, 1H), 5.34-5.23 (m, 1H), 4.99-3-yl)amino)pyrimidin-4- 4.98 (m, 1H), 3.95 (t, J = 13.2 Hz, 2H),yl)pyridin-2- 3.81-3.64 (m, 2H), 3.42-3.33 (m, 1H),yl)oxy)phenyl)butane-1- 3.08 (t, J = 11.7 Hz, 1H), 2.62 (s, 1H),sulfonamide 2.29-2.00 (m, 3H), 1.09 (t, J = 7.5 Hz, 3H) 269 4-(2-(4-556.2 (400 MHz, CD₃OD) δ 8.57 (d, J = 7.5 Hz, Example((ethyl(methyl)sulfamoyl)amino)- 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.20 (m,64 2,3,5-trifluoro-phenoxy)- 1H), 7.45-7.22 (m, 2H), 7.21-7.01 (m,3-pyridyl)-2-(((3S,5S)- 1H), 4.91-4.80 (m, 1H), 4.38 (s, 1H),5-fluoro-3- 3.31-3.22 (m, 3H), 3.14 (t, J = 12.8 Hz,piperidyl)amino)pyrimidine 1H), 2.90 (s, 3H), 2.87-2.68 (m, 1H),2.59-2.49 (m, 1H), 2.41 (s, 1H), 1.95- 1.72 (m, 1H), 1.18 (t, J = 7.1Hz, 3H) 270 2,2-difluoro-N-(2,3,6- 605.2 (300 MHz, CD₃OD) δ 8.62 (s,1H), 8.46 Example trifluoro-4-((3-(2-(((3S,5S)- (d, J = 6.1 Hz, 1H),7.78 (s, 1H), 7.26 (dd, 40 5-fluoropiperidin-3- J = 13.9, 7.6 Hz, 2H),5.30 (d, J = 44.8 yl)amino)pyrimidin-4-yl)-6- Hz, 1H), 3.95 (t, J = 13.2Hz, 2H), 3.68 methylpyridin-2- (d, J = 16.1 Hz, 2H), 3.43 (d, J = 14.3Hz, yl)oxy)phenyl)butane-1- 1H), 3.28 (s, 1H), 3.09 (t, J = 11.6 Hz,sulfonamide 1H), 2.62 (s, 1H), 2.46 (s, 3H), 2.31- 1.96 (m, 3H), 1.09(t, J = 7.5 Hz, 3H) 271 1-(2,2-difluorocyclopropyl)- 589.1 (300 MHz,DMSO-d₆) δ 8.42 (d, J = 5.1 Example N-(2,3,6-trifluoro-4-((3-(2- Hz,2H), 8.27 (dd, J = 4.8, 1.8 Hz, 1H), 40 (((3S,5S)-5-fluoropiperidin-7.44-7.31 (m, 3H), 7.29 (s, 1H), 5.01- 3-yl)amino)pyrimidin-4- 4.86 (m,1H), 4.25 (s, 1H), 3.27 (d, J = yl)pyridin-2- 7.2 Hz, 2H), 3.17 (d, J =10.2 Hz, 2H), yl)oxy)phenyl)methanesulfonamide 3.07 (d, J = 13.5 Hz,2H), 2.92 (d, J = 13.6 Hz, 1H), 2.58 (s, 1H), 2.21 (s, 2H), 1.82-1.72(m, 2H), 1.47 (dd, J = 12.6, 4.5 Hz, 1H) 272 N-(4-((3-(2-(((1r,4r)-4-613.2 (400 MHz, CD₃OD) δ 8.60 (d, J = 6.2 Hz, Example(dimethylamino)cyclohexyl) 1H), 8.42 (d, J = 6.3 Hz, 1H), 8.35 (d, J =38 amino)pyrimidin-4- 5.2 Hz, 1H), 7.65 (d, J = 6.3 Hz, 1H),yl)pyridin-2-yl)oxy)-2,3,6- 7.52 (dd, J = 6.7, 2.8 Hz, 2H), 7.42 (dd, J= trifluorophenyl)-1- 5.1, 2.0 Hz, 4H), 7.27 (t, J = 7.2 Hz,phenylmethanesulfonamide 1H), 4.57 (s, 2H), 3.48-3.41 (s, 2H),hydrochloride 2.90 (s, 6H), 2.34 (d, J = 12.5 Hz, 2H), 2.18 (s, 2H),1.78-1.68 (m, 2H), 1.63 (d, J = 11.1 Hz, 1H), 1.57 (d, J = 11.5 Hz, 1H)273 N-(2,3-difluoro-4-((3-(2- 566.2 (300 MHz, DMSO-d₆) δ 8.38-8.36 (m,Example (((S)-piperidin-3- 2H), 8.20 (dd, J = 4.8, 1.9 Hz, 1H), 7.54- 71yl)amino)pyrimidin-4- 7.36 (m, 5H), 7.34-7.30 (m, 1H), 7.21yl)pyridin-2-yl)oxy)phenyl)- (d, J = 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz,N′-methyl-1- 1H), 7.09-6.94 (m, 2H), 4.64 (s, 2H),phenylmethanesulfonimidamide 3.83 (s, 1H), 3.07 (d, J = 11.9 Hz, 1H),2.78 (d, J = 12.4 Hz, 1H), 2.58 (s, 3H), 2.42-2.36 (m, 2H), 1.89 (s,1H), 1.64- 1.61 (m, 1H), 1.49-1.13 (m, 2H) 274 N-(2,3-difluoro-4-((3-(2-566.2 (300 MHz, DMSO-d₆) δ 8.37 (d, J = 5.1 Example (((S)-piperidin-3-Hz, 2H), 8.20 (dd, J = 4.8, 1.9 Hz, 1H), 71 yl)amino)pyrimidin-4-7.54-(m, 5H), 7.32 (dd, J = 7.5, 4.8 Hz, yl)pyridin-2-yl)oxy)phenyl)-1H), 7.21 (d, J = 5.1 Hz, 1H), 7.13 (d, J = N′-methyl-1- 8.0 Hz, 1H),7.08-6.95 (m, 2H), 4.64 (s, phenylmethanesulfonimidamide 2H), 3.83 (s,1H), 3.07 (d, J = 11.7 Hz, 1H), 2.78 (d, J = 12.5 Hz, 1H), 2.58 (s, 3H),2.51-2.32 (m, 2H), 1.90 (s, 1H), 1.64-1.61 (m, 1H), 1.49-1.13 (m, 2H)275 1-(2-fluorophenyl)-N-(2,3,6- 621.1 (300 MHz, CD₃OD) δ 8.55 (d, J =7.5 Hz, Example trifluoro-4-((3-(2-(((3S,5S)- 1H), 8.37 (d, J = 5.2 Hz,1H), 8.21-8.19 42 5-fluoro-5-methylpiperidin- (m, 1H), 7.62-7.54 (m,1H), 7.44-7.28 3-yl)amino)pyrimidin-4- (m, 3H), 7.24-7.07 (m, 3H), 4.58(s, yl)pyridin-2- 2H), 4.38 (s, 1H), 3.39-3.37 (m, 1H),yl)oxy)phenyl)methanesulfonamide 3.07 (t, J = 12.0 Hz, 1H), 2.80-2.69(m, 1H), 2.59-2.39 (m, 2H), 1.81-1.52 (m, 1H), 1.37 (d, J = 21.0 Hz, 3H)276 1-(4-((3-(2-(((3S,5S)-5- 568.2 (400 MHz, DMSO-d₆) δ 9.09 (s, 1H),8.86 Example Fluoropiperidin-3- (s, 1H), 8.38 (d, J = 5.1 Hz, 2H), 8.25-73 yl)amino)pyrimidin-4- 8.20 (m, 1H), 8.03 (d, J = 2.3 Hz, 1H),yl)pyridin-2-yl)oxy)phenyl)-3-(3- 7.59 (d, J = 8.6 Hz, 1H), 7.55-7.47(m, (trifluoromethyl)phenyl)urea 3H), 7.34-7.25 (m, 3H), 7.19 (d, J =8.0 Hz, 1H), 7.14-7.09 (m, 2H), 4.87-4.74 (m, 1H), 4.15 (s, 1H), 3.05(d, J = 12.1 Hz, 1H), 2.95-2.85 (m, 1H), 2.73-2.65 (m, 1H), 2.47-2.29(m, 1H), 2.15 (s, 1H), 1.90-1.75 (m, 1H) 2771-phenyl-N-(2,3,6-trifluoro- 603.2 (400 MHz, CD₃OD) δ 8.52 (dd, J = 7.6,Example 4-((3-(2-((5- 1.9 Hz, 1H), 8.39 (d, J = 5.3 Hz, 1H), 74(fluoromethyl)piperidin-3- 8.20 (dd, J = 4.8, 1.9 Hz, 1H), 7.55-7.48yl)amino)pyrimidin-4- (m, 2H), 7.43-7.35 (m, 4H), 7.32 (dd, J =yl)pyridin-2- 7.5, 4.8 Hz, 1H), 7.09-7.00 (m, 1H),yl)oxy)phenyl)methanesulfonamide 4.50-4.40 (m, 3H), 4.32-4.26 (m, 2H),3.25 (d, J = 13.4 Hz, 1H), 3.21-3.13 (m, 1H), 2.99 (dd, J = 13.0, 3.0Hz, 1H), 2.68 (dd, J = 12.6, 9.9 Hz, 1H), 2.24 (s, 1H), 2.00 (d, J =13.9 Hz, 1H), 1.79-1.68 (m, 1H) 278 1-phenyl-N-(2,3,6-trifluoro- 603.2(400 MHz, CD₃OD) δ 8.52 (dd, J = 7.6, Example 4-((3-(2-((5- 1.9 Hz, 1H),8.39 (d, J = 5.3 Hz, 1H), 74 (fluoromethyl)piperidin-3- 8.20 (dd, J =4.8, 1.9 Hz, 1H), 7.55-7.48 yl)amino)pyrimidin-4- (m, 2H), 7.43-7.35 (m,4H), 7.32 (dd, J = yl)pyridin-2- 7.5, 4.8 Hz, 1H), 7.09-7.00 (m, 1H),yl)oxy)phenyl)methanesulfonamide 4.50-4.40 (m, 3H), 4.32-4.26 (m, 2H),3.25 (d, J = 13.4 Hz, 1H), 3.21-3.13 (m, 1H), 2.99 (dd, J = 13.0, 3.0Hz, 1H), 2.68 (dd, J = 12.6, 9.9 Hz, 1H), 2.24 (s, 1H), 2.00 (d, J =13.9 Hz, 1H), 1.79-1.68 (m, 1H) 279 N-(2,3-difluoro-4-((3-(2- 599.2 (400MHz, CD₃OD) δ 8.59 (d, J = 7.6 Hz, Example (((3S,5S)-5-fluoro-5- 1H),8.37 (d, J = 5.2 Hz, 1H), 8.20-8.10 42 methylpiperidin-3- (m, 1H),7.45-7.39 (m, 4H), 7.42-7.32 yl)amino)pyrimidin-4- (m, 3H), 7.34-7.24(m, 1H), 7.08-7.01 yl)pyridin-2-yl)oxy)-6- (m, 1H), 4.50 (s, 2H), 4.36(s, 1H), 3.36- methylphenyl)-1- 3.32 (m, 1H), 3.02 (t, J = 12.5 Hz, 1H),phenylmethane sulfonamide 2.68-2.58 (m, 1H), 2.41-2.35 (m, 2H), 2.09 (s,3H), 1.71-1.61 (m, 1H), 1.36 (d, J = 20.9 Hz, 3H) 280N-(2,3-difluoro-4-((3-(2- 585.1 (400 MHz, CD₃OD) δ 8.60 (d, J = 7.5 Hz,Example (((3S,5S)-5-fluoropiperidin- 1H), 8.37 (d, J = 5.3 Hz, 1H),8.16-8.15 40 3-yl)amino)pyrimidin-4- (m, 1H), 7.46-7.33 (m, 7H),7.34-7.24 yl)pyridin-2-yl)oxy)-6- (m, 1H), 7.08-7.01 (m, 1H), 4.94-4.82methylphenyl)-1- (m, 1H), 4.50 (s, 2H), 4.39 (s, 1H), 3.15-3.13 (m, 1H),phenylmethanesulfonamide 2.85-2.75 (m, 1H), 2.58-2.47 (m, 1H), 2.41-2.40(m, 1H), 2.09 (t, J = 1.0 Hz, 3H), 1.94-1.74 (m, 1H) 2811-(2,4-difluorophenyl)-N- 639.1 (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.38Example (2,3,6-trifluoro-4-((3-(2- (d, J = 5.2 Hz, 1H), 8.21 (m, 1H),7.66- 42 (((3S,5S)-5-fluoro-5- 7.52 (m, 1H), 7.41-7.26 (m, 2H), 7.13 (t,methylpiperidin-3- J = 8.3 Hz, 1H), 7.07-6.90 (m, 2H), 4.55yl)amino)pyrimidin-4- (s, 2H), 4.38 (s, 1H), 3.39-3.33 (m, 1H),yl)pyridin-2- 3.17-3.01 (m, 1H), 2.80-2.69 (m, 1H),yl)oxy)phenyl)methanesulfonamide 2.43 (t, J = 12.2 Hz, 2H), 1.80-1.68(m, 1H), 1.45-1.24 (m, 3H) 282 1-(2,6-difluorophenyl)-N- 639.2 (400 MHz,CD₃OD) δ 8.56 (d, J = 7.6 Hz, Example (2,3,6-trifluoro-4-((3-(2- 1H),8.37 (d, J = 5.2 Hz, 1H), 8.20 (dd, J = 42 (((3S,5S)-5-fluoro-5- 4.8,2.0 Hz, 1H), 7.45-7.34 (m, 2H), methylpiperidin-3- 7.31 (dd, J = 7.6,4.8 Hz, 1H), 7.06-6.97 yl)amino)pyrimidin-4- (m, 3H), 4.56 (s, 2H), 4.36(s, 1H), 3.41- yl)pyridin-2- 3.33 (m, 1H), 3.03 (t, J = 12.4 Hz, 1H),yl)oxy)phenyl)methanesulfonamide 2.73-2.64 (m, 1H), 2.42-2.36 (m, 2H),1.74-1.59 (m, 1H), 1.39-1.31 (m, 3H) 283 N-(2,3-difluoro-4-((3-(2- 621.1(400 MHz, CD₃OD) δ 8.60 (d, J = 7.5 Hz, Example(((3S,5S)-5-fluoropiperidin- 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.21-8.11 403-yl)amino)pyrimidin-4- (m, 1H), 7.49-7.37 (m, 2H), 7.34-7.24yl)pyridin-2-yl)oxy)-5- (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.08-methylphenyl)-1-(2,6- 6.98 (m, 2H), 5.00 (s, 1H), 4.65 (s, 2H),difluorophenyl)methanesulfonamide 4.44 (s, 1H), 3.38 (d, J = 13.7 Hz,1H), 3.22 (t, J = 12.7 Hz, 1H), 2.93-2.83 (m, 1H), 2.65-2.54 (m, 1H),2.44 (s, 1H), 2.09 (t, J = 1.0 Hz, 3H), 1.97-1.76 (m, 1H) 2841-p-tolyl-N-(2,3,6-trifluoro- 617.1 (300 MHz, CD₃OD) δ 8.54 (d, J = 7.5Hz, Example 4-((3-(2-(((3S,5S)-5-fluoro- 1H), 8.36 (d, J = 5.4 Hz, 1H),8.19 (m, 42 5-methylpiperidin-3- 1H), 7.44-7.26 (m, 4H), 7.17 (m, 3H),yl)amino)pyrimidin-4- 4.46 (s, 2H), 4.37 (s, 1H), 3.39-3.33 (m,yl)pyridin-2- 1H), 3.15-3.07 (m, 1H), 2.79-2.59 (m,yl)oxy)phenyl)methanesulfonamide 1H), 2.50-2.31 (m, 5H), 1.67 (m, 1H),1.37 (d, J = 21.0 Hz, 3H) 285 1-(4-((3-(2-(((3S,5S)-5- 680.3 (400 MHz,CD₃OD) δ 8.74 (s, 1H), 8.50 Example fluoropiperidin-3- (d, J = 6.5 Hz,1H), 8.33 (dd, J = 4.8, 1.9 81 yl)amino)pyrimidin-4- Hz, 1H), 8.10 (d, J= 2.2 Hz, 1H), 8.01- yl)pyridin-2-yl)oxy)phenyl)- 7.88 (m, 2H), 7.80 (d,J = 8.5 Hz, 1H), 3-(4-((4-methylpiperazin-1- 7.60-7.55 (m, 2H), 7.36(dd, J = 7.7, 4.8 yl)methyl)-3- Hz, 1H), 7.21-7.14 (m, 2H), 5.32 (d, J =(trifluoromethyl)phenyl)urea 44.9 Hz, 1H), 4.93 (s, 1H), 4.37 (s, 2H),hydrochloride 3.87-3.65 (m, 4H), 3.65-3.40 (m, 5H), 3.36 (d, J = 3.3 Hz,2H), 3.14 (t, J = 11.9 Hz, 1H), 3.01 (s, 3H), 2.64 (s, 1H), 2.16 (dt, J= 43.0, 13.9 Hz, 1H) 286 1-(3-((3-(2-(((3S,5S)-5- 680.3 (400 MHz, CD₃OD)δ 8.74 (d, J = 7.1 Hz, Example fluoropiperidin-3- 1H), 8.51 (d, J = 6.5Hz, 1H), 8.36 (dd, J = 81 yl)amino)pyrimidin-4- 4.8, 1.9 Hz, 1H), 8.10(d, J = 2.2 Hz, yl)pyridin-2-yl)oxy)phenyl)- 1H), 7.95 (d, J = 8.2 Hz,2H), 7.79 (d, J = 3-(4-((4-methylpiperazin-1- 8.5 Hz, 1H), 7.59 (t, J =2.2 Hz, 1H), 7.44- yl)methyl)-3- 7.35 (m, 2H), 7.28-7.22 (m, 1H), 6.92-(trifluoromethyl)phenyl)urea 6.85 (m, 1H), 5.32 (d, J = 44.8 Hz, 1H),hydrochloride 4.95 (s, 1H), 4.46 (s, 2H), 3.94-3.34 (m, 11H), 3.15 (t, J= 12.0 Hz, 1H), 3.02 (s, 3H), 2.65 (s, 1H), 2.17 (dt, J = 42.7, 13.4 Hz,1H) 287 N-(4-((3-(2-((1- 611.2 (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.46Example azabicyclo[3.3.1]nonan-3- (dd, J = 5.8, 2.1 Hz, 1H), 8.28 (d, J= 4.4 38 yl)amino)pyrimidin-4- Hz, 1H), 7.57-7.50(m, 3H), 7.42-7.37yl)pyridin-2-yl)oxy)-2,3,6- (m, 4H), 7.22 (t, J = 8.5 Hz, 1H), 4.88 (s,trifluorophenyl)-1- 1H), 4.87 (s, 1H), 4.73 (s, 1H), 4.55 (s,83phenylmethanesulfonamide 2H), 3.99 (dd, J = 13.0, 6.7 Hz, 1H), 3.63hydrochloride (d, J = 12.8 Hz, 1H), 3.10-3.06 (m, 2H), 2.59-2.50 (m,2H), 2.44-2.31 (m, 1H), 1.88-1.77 (m, 3H), 1.63 (t, J = 12.9 Hz, 1H).288 N-(4-((3-(2-((1- 611.2 (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 8.26Example azabicyclo[3.3.1]nonan-3- (d, J = 4.7 Hz, 1H), 7.43-7.33 (m,7H), 38 yl)amino)pyrimidin-4- 7.23 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 8.1yl)pyridin-2-yl)oxy)-2,3,6- Hz, 1H), 4.76 (s, 1H), 4.33 (s, 2H), 3.42trifluorophenyl)-1- (s, 1H), 3.05 (s, 2H), 2.90-2.78 (m, 3H),phenylmethanesulfonamide 2.11 (s, 1H), 1.84-1.81 (m, 5H), 1.58- 1.53 (m,1H) 290 1-o-tolyl-N-(2,3,6-trifluoro- 617.1 (400 MHz, CD₃OD) δ 8.57 (s,1H), 8.38 Example 4-((3-(2-(((3S,5S)-5-fluoro- (d, J = 5.3 Hz, 1H),8.32-8.22 (m, 1H), 42 5-methylpiperidin-3- 7.44 (d, J = 7.3 Hz, 1H),7.37-7.30 (m, yl)amino)pyrimidin-4- 2H), 7.28-7.14 (m, 4H), 4.61 (s,2H), yl)pyridin-2- 4.40-4.35 (m, 1H), 3.40-3.37 (m, 1H),yl)oxy)phenyl)methanesulfonamide 3.05 (t, J = 11.7 Hz, 1H), 2.50-2.68(m, 1H), 2.48 (s, 3H), 2.45-2.30 (m, 2H), 1.80-1.67 (m, 1H), 1.37 (d, J= 20.9 Hz, 3H) 291 1-(3-methoxyphenyl)-N- 633.2 (400 MHz, CD₃OD) δ 8.56(s, 1H), 8.38 Example (2,3,6-trifluoro-4-((3-(2- (d, J = 5.2 Hz, 1H),8.25-8.21 (m, 1H), 42 (((3S,5S)-5-fluoro-5- 7.38-7.25 (m, 3H), 7.18-7.11(m, 1H), methylpiperidin-3- 7.10-7.05 (m, 2H), 6.97-6.91 (m, 1H),yl)amino)pyrimidin-4- 4.48 (s, 2H), 4.37-4.33 (m, 1H), 3.83 (s,yl)pyridin-2- 3H), 3.37-3.33(m, 1H), 3.05 (t, J = 11.6yl)oxy)phenyl)methanesulfonamide Hz, 1H), 2.70-2.66 (m, 1H), 2.44-2.31(m, 2H), 1.67-1.56 (m, 1H), 1.37 (d, J = 21.0 Hz, 3H) 292N-(2,6-difluoro-4-((3-(2- 599.2 (300 MHz, CD₃OD) δ 8.68 (s, 1H), 8.46Example (((3S,5S)-5-fluoro-5- (d, J = 5.6 Hz, 1H), 8.27 (d, J = 4.6 Hz,42 methylpiperidin-3- 1H), 7.70 (s, 1H), 7.54-7.46 (m, 2H),yl)amino)pyrimidin-4- 7.45-7.32 (m, 4H), 6.95 (d, J = 10.2 Hz,yl)pyridin-2-yl)oxy)-3- 1H), 4.50 (s, 2H), 3.78-3.43 (m, 2H),methylphenyl)-1- 3.27-2.83 (m, 2H), 2.49 (s, 1H), 2.18-phenylmethanesulfonamide 1.80 (m, 4H), 1.54 (d, J = 21.5 Hz, 3H), 1.28(s, 1H) 293 N-(2,6-difluoro-4-((3-(2- 621.1 (300 MHz, CD₃OD) δ 8.58 (d,J = 7.5 Hz, Example (((3S,5S)-5-fluoropiperidin- 1H), 8.37 (d, J = 5.2Hz, 1H), 8.20 (dd, J = 40 3-yl)amino)pyrimidin-4- 4.8, 2.0 Hz, 1H),7.53-7.25 (m, 3H), yl)pyridin-2-yl)oxy)-3- 7.05 (t, J = 8.0 Hz, 2H),6.90 (dd, J = methylphenyl)-1-(2,6- 10.4, 2.2 Hz, 1H), 4.98-4.78 (m,1H), difluorophenyl)methanesulfonamide 4.67 (s, 2H), 4.38 (s, 1H),3.31-3.22 (m, 1H), 3.11 (d, J = 12.2 Hz, 1H), 2.91- 2.68 (m, 1H),2.61-2.33 (m, 2H), 2.08 (d, J = 1.9 Hz, 3H), 1.97-1.67 (m, 1H) 2941-phenyl-N-(2,3,6-trifluoro- 617.2 (300 MHz, DMSO-d₆) δ 8.40 (d, J = 5.1Example 4-((3-(2-((5-(fluoromethyl)- Hz, 2H), 8.32-8.22 (m, 1H),7.48-7.30 88 5-methylpiperidin-3- (m, 7H), 7.29-7.19 (m, 2H), 4.73-4.29yl)amino)pyrimidin-4- (m, 4H), 4.01 (s, 1H), 3.22 (d, J = 11.6yl)pyridin-2- Hz, 1H), 2.84 (d, J = 12.7 Hz, 1H), 2.38-yl)oxy)phenyl)methanesulfonamide 2.28 (m, 2H), 1.92 (d, J = 12.7 Hz,1H), 1.37-1.23 (m, 1H), 0.92 (s, 3H) 295 1-phenyl-N-(2,3,6-trifluoro-617.2 (300 MHz, DMSO-d₆) δ 8.40 (d, J = 5.1 Example4-((3-(2-((5-(fluoromethyl)- Hz, 2H), 8.32-8.22 (m, 1H), 7.48-7.30 885-methylpiperidin-3- (m, 7H), 7.29-7.18 (m, 2H), 4.70-4.29yl)amino)pyrimidin-4- (m, 4H), 4.01 (s, 1H), 3.22 (d, J = 11.4yl)pyridin-2- Hz, 1H), 2.84 (d, J = 12.7 Hz, 1H), 2.31yl)oxy)phenyl)methanesulfonamide (t, J = 11.7 Hz, 2H), 1.92 (d, J = 12.9Hz, 1H), 1.30 (t, J = 12.0 Hz, 1H), 0.92 (s, 3H) 296N-(2-fluoro-4-((3-(2- 583.2 (300 MHz, DMSO-d₆) δ 8.36 (d, J = 5.1Example (((3S,5S)-5-fluoropiperidin- Hz, 1H), 8.26 (dd, J = 4.8, 2.0 Hz,1H), 40 3-yl)amino)pyrimidin-4- 7.48-7.29 (m, 6H), 7.21 (dd, J = 16.5,yl)pyridin-2-yl)oxy)-6- 6.6 Hz, 2H), 6.89-6.81 (m, 1H), 6.79methoxyphenyl)-1- (dd, J = 10.2, 2.5 Hz, 1H), 4.86-4.70 (m,phenylmethanesulfonamide 1H), 4.42 (s, 2H), 4.13 (s, 1H), 3.84 (s, 3H),3.02 (d, J = 12.8 Hz, 2H), 2.88 (t, J = 12.9 Hz, 1H), 2.38 (d, J = 11.0Hz, 2H), 2.12 (s, 1H), 1.92-1.66 (m, 1H) 297 N-(2,3-difluoro-4-((3-(2-613.2 (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.50 Example(((3S,5S)-5-fluoro-5- (m, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.37 42methylpiperidin-3- (dd, J = 7.7, 4.7 Hz, 1H), 7.33-7.27 (m,yl)amino)pyrimidin-4- 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.00-6.93yl)pyridin-2-yl)oxy)-5- (m, 1H), 4.87 (s, 1H), 4.48 (s, 2H), 3.74methylphenyl)-1-(p- (dd, J = 12.1,4.4 Hz, 1H), 3.62-3.52 (m,tolyl)methanesulfonamide 1H), 3.20-3.28 (m, 1H), 2.96 (d, J = 11.9 Hz,1H), 2.53 (m, 1H), 2.33 (s, 3H), 2.11-2.06 (m, 3H), 1.98 (q, J = 12.8Hz, 1H), 4.57 (d, J = 21.6 Hz, 3H) 298 N-(4-((3-(2-((1,1-difluoro-5-633.1 (300 MHz, DMSO-d₆) δ 8.52-8.35 (m, Example azaspiro[2.5]octan-7-2H), 8.29-8.27 (m, 1H), 7.48-7.26 (m, 91 yl)amino)pyrimidin-4- 9H), 4.46(s, 2H), 4.09-3.92 (m, 1H), yl)pyridin-2-yl)oxy)-2,3,6- 3.22-3.17 (m,1H), 2.86-2.82 (m, 1H), trifluorophenyl)-1- 2.74-2.59 (m, 2H), 1.95-1.88(m, 1H), phenylmethanesulfonamide 1.79-1.74 (m, 1H), 1.43-1.24 (m, 2H)299 N-(4-((3-(2-((1,1-difluoro-5- 633.1 (300 MHz, DMSO-d₆) δ 8.52-8.34(m, Example azaspiro[2.5]octan-7- 2H), 8.29-8.27 (m, 1H), 7.48-7.26 (m,91 yl)amino)pyrimidin-4- 9H), 4.45 (s, 2H), 4.02-3.93 (m, 1H),yl)pyridin-2-yl)oxy)-2,3,6- 3.22-3.15 (m, 1H), 2.90-2.52 (m, 3H),trifluorophenyl)-1- 1.96-1.88 (m, 1H), 1.79-1.75 (m, 1H),phenylmethanesulfonamide 1.41-1.24 (m, 2H) 300N-(4-((3-(2-((1,1-difluoro-5- 633.1 (300 MHz, DMSO-d₆) δ 8.61-8.38 (m,Example azaspiro[2.5]octan-7- 2H), 8.28-8.26 (m, 1H), 7.48-7.30 (m, 91yl)amino)pyrimidin-4- 9H), 4.46 (s, 2H), 4.06-3.88 (m, 1H),yl)pyridin-2-yl)oxy)-2,3,6- 3.22-3.17 (m, 1H), 2.84-2.60 (m, 2H),trifluorophenyl)-1- 2.05-1.74 (m, 2H), 1.41-1.19 (m, 3H)phenylmethanesulfonamide 301 N-(4-((3-(2-((1,1-difluoro-5- 633.1 (300MHz, DMSO-d₆) δ 8.50-8.41 (m, Example azaspiro[2.5]octan-7- 2H),8.28-8.24 (m, 1H), 7.51-7.28 (m, 91 yl)amino)pyrimidin-4- 9H), 4.45 (s,2H), 4.06-3.82 (m, 1H), yl)pyridin-2-yl)oxy)-2,3,6- 3.22-3.12 (m, 1H),2.83-2.52 (m, 2H), trifluorophenyl)-1- 2.00-1.78 (m, 2H), 1.41-1.19 (m,3H) phenylmethanesulfonamide 302 N-(4-((3-(2-((5- 621.2 (400 MHz, CD₃OD)δ 8.56 (d, J = 7.6 Hz, Example (difluoromethyl)piperidin-3- 1H), 8.38(d, J = 5.2 Hz, 1H), 8.26-8.16 92 yl)amino)pyrimidin-4- (m, 1H),7.56-7.46 (m, 2H), 7.45-7.35 yl)pyridin-2-yl)oxy)-2,3,6- (m, 3H),7.38-7.30 (m, 2H), 7.22-7.12 trifluorophenyl)-1- (m, 1H), 5.79 (td, J =55.6, 3.6 Hz, 1H), phenylmethanesulfonamide 4.52 (s, 2H), 4.13 (s, 1H),3.45-3.35 (m, 1H), 3.18 (d, J = 12.4 Hz, 1H), 2.53 (t, J = 12.0 Hz, 1H),2.49-2.39 (m, 1H), 2.32- 2.18 (m, 2H), 1.51-1.43 (m, 1H) 303N-(4-((3-(2-((5- 621.2 (400 MHz, CD₃OD) δ 8.59 (d, J = 7.5 Hz, Example(difluoromethyl)piperidin-3- 1H), 8.44 (d, J = 5.3 Hz, 1H), 8.29-8.19 92yl)amino)pyrimidin-4- (m, 1H), 7.52 (s, 1H), 7.55-7.48 (m,yl)pyridin-2-yl)oxy)-2,3,6- 1H), 7.47-7.37 (m, 4H), 7.41-7.31 (dd,trifluorophenyl)-1- J = 7.6.05 5.95, 4.9 Hz, 1H), 7.25-7.15phenylmethane sulfonamide (m, 1H), 6.00 (td, J = 55.6, 3.6 Hz, 1H), 4.55(s, 2H), 4.45 (s, 1H), 3.82-3.72 (m, 1H), 3.56 (d, J = 9.4 Hz, 1H), 2.98(t, J = 12.6 Hz, 1H), 2.84 (t, J = 11.9 Hz, 1H), 2.65-2.54 (m, 1H), 2.37(d, J = 12.8 Hz, 1H), 1.74-1.64 (m, 1H) 304 1-(4-methoxyphenyl)-N- 633.2(300 MHz, CD₃OD) δ 8.56 (d, J = 7.5 Hz, Example(2,3,6-trifluoro-4-((3-(2- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.22-8.21 42(((3S,5S)-5-fluoro-5- (m, 1H), 7.45-7.39 (m, 2H), 7.37-7.31methylpiperidin-3- (m, 2H), 7.18-7.14 (m, 1H), 6.97-6.92yl)amino)pyrimidin-4- (m, 2H), 4.44 (s, 2H), 4.38-4.36 (s, 1H),yl)pyridin-2- 3.82 (s, 3H), 3.39-3.36 (m, 1H), 3.05-2.98yl)oxy)phenyl)methanesulfonamide (m, 1H), 2.70-2.64 (m, 1H), 2.50- 2.39(m, 2H), 1.79-1.52 (m, 1H), 1.37 (d, J = 21.0 Hz, 3H) 305N-(2,3-difluoro-4-((3-(2- 613.2 (300 MHz, CD₃OD) δ 8.59 (d, J = 7.3 Hz,Example (((3S,5S)-5-fluoro-5- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.17-8.1542 methylpiperidin-3- (m, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.32-yl)amino)pyrimidin-4- 7.27 (m, 3H), 7.17 (d, J = 7.8 Hz, 2H),yl)pyridin-2-yl)oxy)-6- 7.01-6.95 (m, 1H), 4.46 (s, 2H), 4.36 (s,methylphenyl)-1-(p- 1H), 3.36-3.35 (m, 1H), 3.01-3.95 (m,tolyl)methanesulfonamide 1H), 2.70-2.62 (m, 1H), 2.44-2.27 (m, 5H), 2.07(s, 3H), 1.75-1.55 (m, 1H), 1.36 (d, J = 20.9 Hz, 3H) 306N-(4-((3-(2-((4- 631.2 (300 MHz, CD₃OD) δ 8.51 (dd, J = 7.6, Example(dimethylamino)-3- 1.9 Hz, 1H), 8.37 (d, J = 5.2 Hz, 1H), 95fluorocyclohexyl)amino)pyrimidin- 8.19 (dd, J = 4.9, 2.0 Hz, 1H),7.54-7.44 4-yl)pyridin-2- (m, 2H), 7.42-7.25 (m, 5H), 7.16-7.05yl)oxy)-2,3,6- (m, 1H), 5.14-4.90 (m, 1H), 4.48 (s, trifluorophenyl)-1-2H), 4.34 (s, 1H), 2.78-2.62 (m, 1H), phenylmethanesulfonamide 2.50-2.31(m, 7H), 2.06-1.59 (m, 5H) 307 N-(4-((3-(2-((4- 631.3 (300 MHz, CD₃OD) δ8.59 (dd, J = 7.7, Example (dimethylamino)-3- 1.9 Hz, 1H), 8.50 (d, J =6.5 Hz, 0H), 95 fluorocyclohexyl)amino)pyrimidin- 8.43 (dd, J = 6.5, 2.9Hz, 1H), 8.34 (dd, J = 4-yl)pyridin-2- 4.8, 2.0 Hz, 1H), 7.71 (d, J =6.5 Hz, yl)oxy)-2,3,6- 1H), 7.50 (dd, J = 6.6, 3.0 Hz, 2H), 7.45-7.34(m, 4H), trifluorophenyl)-1- 7.30-7.16 (m, 1H), 5.66-5.27 (m, 1H), 4.54(s, 2H), 3.54 (dd, J = phenylmethanesulfonamide 31.5, 10.5 Hz, 1H), 3.00(d, J = 7.3 Hz, hydrochloride 6H), 2.65 (s, 5H), 2.40-1.56 (m, 6H) 308N-(4-((3-(2-((4- 631.3 (300 MHz, CD₃OD) δ 8.51 (dd, J = 7.6, Example(dimethylamino)-3- 1.9 Hz, 1H), 8.37 (d, J = 5.2 Hz, 1H), 95fluorocyclohexyl)amino)pyrimidin- 8.19 (dd, J = 4.9, 2.0 Hz, 1H), 7.49(dd, J = 4-yl)pyridin-2- 7.0, 2.6 Hz, 2H), 7.42-7.23 (m, 5H),yl)oxy)-2,3,6- 7.18-7.03 (m, 1H), 5.14-4.87 (m, 1H), trifluorophenyl)-1-4.48 (s, 2H), 4.34 (s, 1H), 2.78-2.61 (m, phenylmethanesulfonamide 1H),2.51-2.30 (m, 7H), 2.06-1.53 (m, 5H) 309 N-(4-((3-(2-(((1r,4r)-4- 565.2(300 MHz, DMSO-d₆) δ 8.41-8.37 (m, Example (dimethylamino)cyclohexyl)2H), 8.26 (dd, J = 4.8, 1.9 Hz, 1H), 7.41- 38 amino)pyrimidin-4- 7.34(m, 2H), 7.23-7.17 (m, 2H), 3.71 yl)pyridin-2-yl)oxy)-2,3,6- (s, 1H),3.05 (dd, J = 9.2, 6.2 Hz, 2H), trifluorophenyl)propane-1- 2.36 (s, 1H),2.31 (s, 6H), 2.11-2.03 (m, sulfonamide 2H), 1.86-1.74 (m, 4H),1.39-1.28 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H) 310 N-(4-((3-(2-(((1r,4r)-4-615.2 (300 MHz, CD₃OD) δ 8.62 (dd, J = 7.7, Example(dimethylamino)cyclohexyl) 1.9 Hz, 1H), 8.41 (d, J = 6.7 Hz, 1H), 38amino)pyrimidin-4- 8.36 (dd, J = 4.9, 1.9 Hz, 1H), 7.72 (d, J =yl)pyridin-2-yl)oxy)-2,3,6- 6.6 Hz, 1H), 7.42 (dd, J = 7.7, 4.9 Hz,trifluorophenyl)-3,3- 1H), 7.35-7.17 (m, 1H), 3.48-3.38 (m,difluorobutane-1- 2H), 3.36-3.33 (m, 1H), 3.30-3.32 (m, sulfonamide 1H),2.90 (s, 6H), 2.63-2.41 (m, 2H), 2.36-2.32 (m, 2H), 2.21-2.17 (m, 2H),1.77-1.61 (m, 7H) 311 N-(2,5-difluoro-4-((3-(2- 613.2 (300 MHz, CD₃OD) δ8.56 (s, 1H), 8.36 Example (((3S,5S)-5-fluoro-5- (d, J = 5.1 Hz, 1H),8.14 (dd, J = 4.6, 1.9 42 methylpiperidin-3- Hz, 1H), 7.39 (d, J = 5.1Hz, 1H), 7.33-7.23 (m, 3H), yl)amino)pyrimidin-4- 7.16-7.06 (m, 3H),4.45- yl)pyridin-2-yl)oxy)-3- 4.36 (m, 3H), 3.36-3.32 (m, 2H), 3.09-methylphenyl)-1-(p- 3.01 (m, 1H), 2.57 (d, J = 14.1 Hz, 1H),tolyl)methanesulfonamide 2.36-2.32 (m, 5H), 2.12 (d, J = 2.4 Hz, 3H),1.39-1.33 (m, 3H) 312 1-(4- 667.1 (300 MHz, CD₃OD) δ 8.55 (d, J = 7.5Hz, Example (methylsulfonyl)phenyl)-N- 1H), 8.37 (d, J = 5.2 Hz, 1H),8.19 (dd, J = 98 (2,3,6-trifluoro-4-((3-(2- 4.9, 1.9 Hz, 1H), 8.02-7.92(m, 2H), (((3S,5S)-5-fluoropiperidin- 7.81-7.72 (m, 2H), 7.40-7.26 (m,2H), 3-yl)amino)pyrimidin-4- 7.13-7.07 (m, 1H), 5.03-4.87 (m, 1H),yl)pyridin-2- 4.59 (s, 2H), 4.43 (s, 1H), 3.38 (d, J =yl)oxy)phenyl)methanesulfonamide 15.4 Hz, 1H), 3.22 (t, J = 12.9 Hz,1H), 3.13 (s, 3H), 2.95-2.82 (m, 1H), 2.67- 2.53 (m, 1H), 2.43-2.39 (m,1H), 1.92- 1.79 (m 1H) 313 N-(2,3-difluoro-4-((3-(2- 599.2 (300 MHz,DMSO-d₆) δ 9.73 (s, 1H), 9.72- Example (((3S,5S)-5-fluoropiperidin- 9.55(m, 1H), 9.38-9.11 (m, 1H), 8.70- 99 3-yl)amino)pyrimidin-4- 8.21 (m,3H), 7.65-7.62 (m, 1H), 7.47- yl)pyridin-2-yl)oxy)-5- 7.31 (m, 7H),6.84-6.81 (m, 1H), 5.17- methylphenyl)-1- 5.14 (m, 1H), 4.62-4.50 (m,2H), 3.54- phenylethane-1-sulfonamide 3.17 (m, 3H), 2.85-2.73 (m, 1H),2.41- hydrochloride 2.23 (m, 1H), 2.02 (s, 3H), 2.01-1.82 (m, 1H), 1.72(d, J = 6.9 Hz, 3H) 314 N-(2,3-difluoro-4-((3-(2- 599.2 (300 MHz,DMSO-d₆) δ 8.50-8.41 (m, Example (((3S,5S)-5-fluoropiperidin- 2H),8.23-8.20(m, 1H), 7.46-7.24 (m, 99 3-yl)amino)pyrimidin-4- 8H),6.88-6.85 (m, 1H), 4.92-4.73 (m, yl)pyridin-2-yl)oxy)-5- 1H), 4.55-4.53(m, 1H), 4.20-4.18 (m, methylphenyl)-1- 1H), 3.12-2.65 (m, 4H),2.47-2.42 (m, phenylethane-1-sulfonamide 1H), 2.28-2.08 (m, 1H), 2.04(s, 3H), 1.90-1.74 (m, 1H), 1.72 (d, J = 6.9 Hz, 3H) 3151-(4-cyclopropylphenyl)-N- 629.1 (300 MHz, CD₃OD) δ 8.54 (d, J = 7.5 Hz,Example (2,3,6-trifluoro-4-((3-(2- 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.19(dd, J = 98 (((3S,5S)-5-fluoropiperidin- 4.8, 1.9 Hz, 1H), 7.40-7.26 (m,4H), 3-yl)amino)pyrimidin-4- 7.10 (t, J = 8.9 Hz, 3H), 5.00-4.69 (m,yl)pyridin-2- 1H), 4.48-4.30 (m, 3H), 3.36-3.30 (m,yl)oxy)phenyl)methanesulfonamide 1H), 3.15 (t, J = 12.9 Hz, 1H),2.93-2.65 (m, 1H), 2.53 (t, J = 11.4 Hz, 1H), 2.46- 2.30 (m, 1H),2.03-1.64 (m, 2H), 1.06- 0.90 (m, 2H), 0.75-0.54 (m, 2H) 3161-(4-fluorophenyl)-N-(2,3,6- 621.1 (300 MHz, CD₃OD) δ 8.52 (d, J = 7.6Hz, Example trifluoro-4-((3-(2-(((3S,5R)- 1H), 8.36 (d, J = 5.2 Hz, 1H),8.19 (dd, J = 61 5-(fluoromethyl)piperidin-3- 4.8, 1.9 Hz, 1H),7.55-7.46 (m, 2H), yl)amino)pyrimidin-4- 7.36-7.26 (m, 2H), 7.17-7.02(m, 3H), yl)pyridin-2- 4.45 (s, 3H), 4.41-4.08 (m, 2H), 3.67-yl)oxy)phenyl)methanesulfonamide 3.43 (m, 1H), 3.26-3.16 (m, 1H), 2.61-2.35 (m, 2H), 2.27-2.06 (m, 2H), 1.46- 1.20 (m, 1H) 3171-phenyl-N-(2,3,6-trifluoro- 601.2 (400 MHz, CD₃OD) δ 8.53 (d, J = 7.5Hz, Example 4-((3-(2-((5- 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.19 (dd, J =108 methoxypiperidin-3- 4.8, 1.9 Hz, 1H), 7.58-7.43 (m, 2H),yl)amino)pyrimidin-4- 7.43-7.22 (m, 5H), 7.05 (ddd, J = 10.3,yl)pyridin-2- 6.8, 2.3 Hz, 1H), 4.44 (s, 2H), 4.41-4.35yl)oxy)phenyl)methanesulfonamide (m, 1H), 3.66-3.62 (m, 1H), 3.42 (s,3H), 3.30 (d, J = 4.0 Hz, 1H), 3.11 (d, J = 13.5 Hz, 1H), 2.82 (dd, J =13.5, 2.1 Hz, 1H), 2.61 (dd, J = 12.4, 10.0 Hz, 1H), 2.30 (d, J = 13.6Hz, 1H), 1.82-1.69 (m, 1H) 318 1-phenyl-N-(2,3,6-trifluoro- 601.2 (400MHz, CD₃OD) δ 8.54 (s, 1H), 8.49 Example 4-((3-(2-((5- (d, J = 5.6 Hz,1H), 8.28 (dd, J = 4.9, 1.9 108 methoxy piperidin-3- Hz, 1H), 7.60-7.46(m, 3H), 7.45-7.33 yl)amino)pyrimidin-4- (m, 4H), 7.20 (ddd, J = 9.2,6.6, 2.3 Hz, yl)pyridin-2- 1H), 4.55 (s, 3H), 3.86 (s, 1H), 3.54 (s,yl)oxy)phenyl)methanesulfonamide 3H), 3.49 (d, J = 12.7 Hz, 2H), 3.38(dd, J = 12.9, 3.1 Hz, 1H), 3.29 (dd, J = 13.2, 2.3 Hz, 1H), 2.32-2.11(m, 2H) 319 1-phenyl-N-(2,3,6-trifluoro- 601.2 (300 MHz, CD₃OD) δ 8.52(d, J = 7.7 Hz, Example 4-((3-(2-((5- 1H), 8.36 (d, J = 5.2 Hz, 1H),8.18 (dd, J = 108 methoxypiperidin-3- 4.9, 1.9 Hz, 1H), 7.58-7.42 (m,2H), yl)amino)pyrimidin-4- 7.42-7.18 (m, 5H), 7.05 (ddd, J = 9.8,yl)pyridin-2- 6.7, 2.3 Hz, 1H), 4.43 (s, 2H), 4.41-4.35yl)oxy)phenyl)methanesulfonamide (m, 1H), 3.66-3.62 (m, 1H), 3.40 (s,3H), 3.30 (d, J = 4.0 Hz, 1H), 3.10 (d, J = 13.3 Hz, 1H), 2.81 (dd, J =13.4, 2.1 Hz, 1H), 2.60 (dd, J = 12.5, 10.0 Hz, 1H), 2.29 (d, J = 13.2Hz, 1H), 1.84-1.58 (m, 1H) 320 1-(2,4-difluorophenyl)-N- 639.2 (300 MHz,CD₃OD) δ 8.53 (d, J = 7.6 Hz, Example (2,3,6-trifluoro-4-((3-(2- 1H),8.38 (d, J = 5.2 Hz, 1H), 8.21 (dd, J = 61 (((3S,5R)-5- 4.9, 1.9 Hz,1H), 7.68-7.54 (m, 1H), (fluoromethyl)piperidin-3- 7.44-7.26 (m, 2H),7.15-6.94 (m, 3H), yl)amino)pyrimidin-4- 4.61-4.06 (m, 5H), 3.59-3.43(m, 1H), yl)pyridin-2- 3.32-3.18 (m, 1H), 2.64-2.42 (m, 2H),yl)oxy)phenyl)methanesulfonamide 2.19 (d, J = 12.6 Hz, 2H), 1.52-1.26(m, 1H). 321 1-(4-cyanophenyl)-N-(2,3,6- 628.2 (300 MHz, CD₃OD) δ 8.52(d, J = 7.2 Hz, Example trifluoro-4-((3-(2-(((3S,5R)- 1H), 8.38 (d, J =5.3 Hz, 1H), 8.25-8.20 61 5-(fluoromethyl)piperidin-3- (m, 1H),7.81-7.71 (m, 4H), 7.39-7.26 yl)amino)pyrimidin-4- (m, 2H), 7.09-6.99(m, 1H), 4.52 (s, yl)pyridin-2- 2H), 4.46-4.31 (m, 1H), 4.29-4.11 (m,yl)oxy)phenyl)methanesulfonamide 2H), 3.59-3.50 (m, 1H), 3.29-3.26 (m,1H), 2.76-2.55 (m, 2H), 2.29-2.19 (m, 2H), 1.53-1.42 (m, 1H) 3221-(4-fluoro-2- 621.2 (300 MHz, DMSO-d₆) δ 8.39 (d, J = 5.1 Examplemethylphenyl)-N-(2,3,6- Hz, 2H), 8.28-8.26 (m, 1H), 7.45-7.32 40trifluoro-4-((3-(2-(((3S,5S)- (m, 3H), 7.27 (t, J = 7.0 Hz, 2H), 7.10-5-fluoropiperidin-3- 6.99 (m, 2H), 4.88 (d, J = 47.4 Hz, 1H),yl)amino)pyrimidin-4- 4.43 (s, 2H), 4.21 (s, 1H), 3.20-2.94 (m,yl)pyridin-2- 2H), 2.90-2.73 (m, 1H), 2.55-5.51(m,yl)oxy)phenyl)methanesulfonamide 1H), 2.39 (s, 3H), 2.27-2.19 (m, 1H),1.94-1.74 (m, 1H) 323 N-(6-chloro-2,3-difluoro-4- 623.1 (300 MHz, CD₃OD)δ 8.57 (d, J = 7.5 Hz, Example ((3-(2-(((3S,5S)-5- 1H), 8.39 (d, J = 5.2Hz, 1H), 8.26-8.17 40 fluoropiperidin-3- (m, 1H), 7.66-7.54 (m, 1H),7.47-7.29 yl)amino)pyrimidin-4- (m, 4H), 7.28-7.11 (m, 2H), 5.04-4.78yl)pyridin-2-yl)oxy)phenyl)- (m, 1H), 4.64 (s, 2H), 4.51-4.31 (m, 1-(2-1H), 3.43-3.36 (m, 1H), 3.21 (t, J = 12.8fluorophenyl)methanesulfonamide Hz, 1H), 3.00-2.76 (m, 1H), 2.64-2.54(m, 1H), 2.50-2.31 (m, 1H), 2.02-1.65 (m, 1H) 324 N-(4-((3-(2-((5- 629.2(400 MHz, DMSO-d₆) δ 8.44 (d, J = 5.1 Example cyclopropylpiperidin-3-Hz, 2H), 8.32-8.22 (m, 1H), 8.05 (s, 107 yl)amino)pyrimidin-4- 1H),7.58-7.48 (m, 1H), 7.38-7.26 (m, yl)pyridin-2-yl)oxy)-2,3,6- 4H),7.19-7.10 (m, 2H), 7.13-7.03 (m, trifluorophenyl)-1-(2- 1H), 4.22 (s,3H), 3.31 (d, J = 12.3 Hz, fluorophenyl)methanesulfonamide 2H),3.17-3.07 (m, 1H), 3.07-2.97 (m, 1H), 2.76-2.66 (m, 1H), 2.00-1.96 (m,1H), 1.74-1.64 (m, 1H), 1.23 (d, J = 10.5 Hz, 1H), 0.69-0.59 (m, 1H),0.45- 0.33 (m, 2H), 0.29-0.22 (m, 1H), 0.17- 0.07 (m, 1H) 325N-(4-((3-(2-((5- 629.2 (400 MHz, DMSO-d₆) δ 8.43 (t, J = 7.8 Examplecyclopropylpiperidin-3- Hz, 2H), 8.32-8.22 (m, 1H), 8.18-7.95 107yl)amino)pyrimidin-4- (m, 1H), 7.58-7.48 (m, 1H), 7.43-7.25yl)pyridin-2-yl)oxy)-2,3,6- (m, 4H), 7.21-7.02 (m, 3H), 4.19 (s,trifluorophenyl)-1-(2- 3H), 3.30 (s, 2H), 3.12-3.02 (m, 2H),fluorophenyl)methanesulfonamide 2.80-2.64 (m, 1H), 1.98 (d, J = 13.7 Hz,1H), 1.77-1.64 (m, 1H), 1.23 (d, J = 7.0 Hz, 1H), 0.69-0.59 (m, 1H),0.51-0.34 (m, 2H), 0.26-0.24 (m, 1H), 0.17-0.07 (m, 1H) 326N-(4-((3-(2-((5- 629.2 (400 MHz, DMSO-d₆) δ 8.57-8.03 (m, Examplecyclopropylpiperidin-3- 4H), 7.59-7.48 (m, 1H), 7.47-7.25 (m, 107yl)amino)pyrimidin-4- 4H), 7.22-7.06 (m, 3H), 4.19 (s, 2H),yl)pyridin-2-yl)oxy)-2,3,6- 4.05 (s, 1H), 3.35-3.32 (m, 2H), 3.18 (d,trifluorophenyl)-1-(2- J = 12.1 Hz, 1H), 2.55-2.45 (m, 2H),fluorophenyl)methanesulfonamide 2.09 (d, J = 12.3 Hz, 1H), 1.43-1.33 (m,1H), 1.03 (d, J = 10.8 Hz, 1H), 0.59- 0.55 (m, 1H), 0.41 (d, J = 8.4 Hz,2H), 0.23-0.08 (m, 2H) 327 N-(4-((3-(2-((5- 629.2 (400 MHz, DMSO-d₆) δ8.53-8.21 (m, Example cyclopropylpiperidin-3- 4H), 7.58-7.47 (m, 1H),7.44 (d, J = 7.6 107 yl)amino)pyrimidin-4- Hz, 1H), 7.38-7.28 (m, 3H),7.21-7.07 yl)pyridin-2-yl)oxy)-2,3,6- (m, 3H), 4.19 (s, 2H),4.05 (s,1H), 3.36 (s, trifluorophenyl)-1-(2- 2H), 3.24-3.13 (m, 1H), 2.62-2.40(m, fluorophenyl)methanesulfonamide 2H), 2.09 (d, J = 12.4 Hz, 1H),1.44- 1.34 (m, 1H), 1.06 (s, 1H), 0.60-0.55 (d, J = 8.8 Hz, 1H),0.46-0.37 (m, 2H), 0.15 (s, 2H) 328 1-phenyl-N-(2,3,6-trifluoro- 615.3(300 MHz, CD₃OD) δ 8.54-18.45 (m, Example 4-((3-(2-((5- 1H), 8.40 (d, J= 5.1 Hz, 1H), 8.20 (dd, J = 108 (methoxymethyl)piperidin- 4.8, 2.1 Hz,1H), 7.50 (d, J = 6.0 Hz, 3-yl)amino)pyrimidin-4- 2H), 7.40-7.26 (m,5H), 7.02 (t, J = 8.4 yl)pyridin-2- Hz, 1H), 4.43 (s, 2H), 4.28 (s, 1H),3.34- yl)oxy)phenyl)methanesulfonamide 3.33 (m, 5H), 3.25-3.05 (m, 2H),3.03 (d, J = 12.9 Hz, 1H), 2.75-2.62 (m, 1H), 2.23 (s, 1H), 1.99 (d, J =12.7 Hz, 1H), 1.74 (d, J = 10.3 Hz, 1H) 329 1-phenyl-N-(2,3,6-trifluoro-615.3 (300 MHz, CD₃OD) δ 8.50 (dd, J = 7.5, Example 4-((3-(2-((5- 1.8Hz, 1H), 8.40 (d, J = 5.1 Hz, 1H), 108 (methoxymethyl)piperidin- 8.21(dd, J = 4.8, 1.8 Hz, 1H), 7.54-7.45 3-yl)amino)pyrimidin-4- (m, 2H),7.40-7.27 (m, 5H), 7.09-6.98 yl)pyridin-2- (m, 1H), 4.44 (s, 2H), 4.28(s, 1H), 3.33-3.30 yl)oxy)phenyl)methanesulfonamide (m, 5H), 3.25-3.04(m, 3H), 2.76- 2.63 (m, 1H), 2.23-2.16(m, 1H), 1.75 (d, J = 14.1 Hz,1H), 1.81-1.60 (m, 1H) 330 1-phenyl-N-(2,3,6-trifluoro- 615.3 (300 MHz,CD₃OD) δ 8.52-8.18 (m, Example 4-((3-(2-((5- 3H), 7.48-7.05 (m, 8H),4.43 (s, 2H), 108 (methoxymethyl)piperidin- 4.15 (s, 1H), 3.54-3.52(m,4H), 3.12- 3-yl)amino)pyrimidin-4- 3.10 (m, 3H), 2.44 (d, J = 12.3Hz, 2H), yl)pyridin-2- 2.07 (s, 2H), 1.30 (d, J = 10.8 Hz, 1H)yl)oxy)phenyl)methanesulfonamide 331 1-phenyl-N-(2,3,6-trifluoro- 615.3(300 MHz, CD₃OD) δ 8.51-8.19 (m, Example 4-((3-(2-((5- 3H), 7.49-7.27(m, 8H), 4.81-4.75 (m, 108 (methoxymethyl)piperidin- 2H), 4.42 (s, 2H),4.14 (s, 1H), 3.56- 3-yl)amino)pyrimidin-4- 3.45 (m, 2H), 3.20-3.07 (m,3H), 2.50- yl)pyridin-2- 2.41 (m, 2H), 2.18-2.04 (m, 2H), 1.36yl)oxy)phenyl)methanesulfonamide (s, 1H) 332 N-(3-chloro-2,6-difluoro-4-623.1 (300 MHz, CD₃OD) δ 8.57 (d, J = 7.5 Hz, Example((3-(2-(((3S,5S)-5- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.23-8.13 112fluoropiperidin-3- (m, 1H), 7.64-7.53 (m, 1H), 7.46-7.28yl)amino)pyrimidin-4- (m, 3H), 7.25-7.09 (m, 3H), 4.99-4.87yl)pyridin-2-yl)oxy)phenyl)- (m, 1H), 4.58 (s, 2H), 4.40 (s, 1H), 3.331-(2- (s, 1H), 3.17 (t, J = 12.9 Hz, 1H), 2.89-fluorophenyl)methanesulfonamide 2.79 (m, 1H), 2.55 (t, J = 11.5 Hz, 1H),2.41 (s, 1H), 1.89-1.79 (m, 1H) 333 1-phenyl-N-(2,3,6-trifluoro- 613.2(300 MHz, CD₃OD) δ 8.58-8.46 (m, Example 4-((3-(2-((5-(2- 2H), 8.29-8.27(m, 1H), 7.59-7.31 (m, 108 fluoropropan-2-yl)piperidin- 7H), 7.23-7.12(m, 1H), 4.54 (s, 3H), 3-yl)amino)pyrimidin-4- 3.81 (d, J = 13.2Hz, 1H),3.51-3.49 (m, yl)pyridin-2- 1H), 3.20 (d, J = 14.4 Hz, 1H), 3.05-yl)oxy)phenyl)methanesulfonamide 3.01 (m, 1H), 2.60-2.47 (m, 1H), 2.21hydrochloride (d, J = 14.1 Hz, 1H), 1.98-1.84 (m, 1H), 1.51-1.42 (m, 6H)334 1-phenyl-N-(2,3,6-trifluoro- 613.2 (300 MHz, CD₃OD) δ 8.58-8.46 (s,Example 4-((3-(2-((5-(2- 2H), 8.29-8.27 (m, 1H), 7.59-7.31 (m, 108fluoropropan-2-yl)piperidin- 7H), 7.23-7.12 (m, 1H), 4.54 (s, 3H),3-yl)amino)pyrimidin-4- 3.81 (d, J = 13.2Hz, 1H), 3.51-3.49 (m,yl)pyridin-2- 1H), 3.20 (d, J = 14.4 Hz, 1H), 3.05-yl)oxy)phenyl)methanesulfonamide 3.01 (m, 1H), 2.60-2.47 (m, 1H), 2.21hydrochloride (d, J = 14.1 Hz, 1H), 1.98-1.84 (m, 1H), 1.51-1.42 (m, 6H)335 1-phenyl-N-(2,3,6-trifluoro- 613.2 (300 MHz, CD₃OD) δ 8.62 (s, 1H),8.47 Example 4-((3-(2-((5-(2- (d, J = 5.7 Hz, 1H), 8.29 (d, J = 3.6 Hz,108 fluoropropan-2-yl)piperidin- 1H), 7.58 (s, 1H), 7.55-7.46 (m, 2H),3-yl)amino)pyrimidin-4- 7.45-7.35 (m, 4H), 7.23 (t, J = 9.6 Hz,yl)pyridin-2- 1H), 4.56-4.41 (m, 3H), 3.86-3.76 (m,yl)oxy)phenyl)methanesulfonamide 1H), 3.63-3.60 (m, 1H), 2.95-2.88 (m,hydrochloride 2H), 2.50-2.31 (m, 2H), 1.75-1.65 (m, 1H), 1.57-1.44 (m,6H) 336 1-phenyl-N-(2,3,6-trifluoro- 613.2 (300 MHz, CD₃OD) δ 8.62 (s,1H), 8.46 Example 4-((3-(2-((5-(2- (d, J = 5.5 Hz, 1H), 8.33-8.25 (m,1H), 108 fluoropropan-2-yl)piperidin- 7.60-7.50 (m, 3H), 7.45-7.35 (m,4H), 3-yl)amino)pyrimidin-4- 7.30-7.16 (m, 1H), 4.56 (s, 3H), 3.85-yl)pyridin-2- 3.49 (m, 2H), 3.02-2.76 (m, 2H), 2.43-2.17 (m, 2H),yl)oxy)phenyl)methanesulfonamide 1.72-1.56 (m, 1H), 1.52-1.34 (m, 6H)hydrochloride 337 N-(4-((3-(2-((5-(1,1- 635.2 (300 MHz, CD₃OD) δ8.53-8.50 (m, Example difluoroethyl)piperidin-3- 2H), 8.28-8.26 (m, 1H),7.55-7.50 (m, 108 yl)amino)pyrimidin-4- 3H), 7.43-7.36 (m, 4H),7.23-7.16 (m, yl)pyridin-2-yl)oxy)-2,3,6- 1H), 4.57 (s, 2H), 4.56-4.49(m, 1H), trifluorophenyl)-1- 3.88-3.84 (m, 1H), 3.56-3.52 (m, 1H),phenylmethanesulfonamide 3.27-3.23 (m, 1H), 3.16-3.12 (m, 1H),hydrochloride 2.92-2.73 (m, 1H), 2.33-2.28 (m, 1H), 2.09-2.00 (m, 1H),1.79-1.66 (m, 3H) 338 N-(4-((3-(2-((5-(1,1- 635.2 (300 MHz, CD₃OD) δ8.57-8.53 (m, Example difluoroethyl)piperidin-3- 1H), 8.45-8.43 (m, 1H),8.25-8.22 (m, 108 yl)amino)pyrimidin-4- 1H),7.54-7.50 (m, 2H), 7.43-7.33(m, yl)pyridin-2-yl)oxy)-2,3,6- 5H), 7.23-7.16 (m, 1H), 4.55 (s, 2H),trifluorophenyl)-1- 4.41-4.23 (m, 1H), 3.76-3.71 (m, 1H),phenylmethanesulfonamide 3.60-3.57 (m, 1H), 2.98-2.76 (m, 2H), 2.62-2.38(m, 2H), 1.77-1.62 (m, 4H) 339 N-(4-((3-(2-((5-(1,1- 635.2 (300 MHz,CD₃OD) δ 8.57-8.53 (m, Example difluoroethyl)piperidin-3- 1H), 8.43-8.38(m, 1H), 8.23-8.22 (m, 108 yl)amino)pyrimidin-4- 1H), 7.54-7.50 (m, 2H),7.43-7.33 (m, yl)pyridin-2-yl)oxy)-2,3,6- 5H), 7.23-7.16 (m, 1H), 4.53(s, 2H), trifluorophenyl)-1- 4.27-4.11 (m, 1H), 3.53-3.49 (m, 1H),phenylmethanesulfonamide 3.30-3.25 (m, 1H), 2.66-2.25 (m, 4H), 1.70-1.50(m, 4H) 340 N-(5-chloro-2,3-difluoro-4- 623.1 (300 MHz, CD₃OD) δ 8.59(d, J = 7.5 Hz, Example ((3-(2-(((3S,5S)-5- 1H), 8.39 (d, J = 5.2 Hz,1H), 8.17 (dd, J = 112 fluoropiperidin-3- 4.8, 1.8 Hz, 1H), 7.56-7.42(m, 2H), yl)amino)pyrimidin-4- 7.42-7.26 (m, 3H), 7.23-7.05 (m, 2H),yl)pyridin-2-yl)oxy)phenyl)-1-(2- 5.02-4.86 (m, 1H), 4.56 (s, 2H), 4.44(s, fluorophenyl)methanesulfonamide 1H), 3.43-3.32 (m, 1H), 3.22 (t, J =12.6 Hz, 1H), 2.95 (d, J = 14.4 Hz, 1H), 2.82 (d, J = 14.7 Hz, 1H), 2.59(t, J = 11.4 Hz, 1H), 1.93-1.72 (m, 1H) 341 1-(4-fluorophenyl)-N-(2,3,6-675.3 (300 MHz, CD₃OD) δ 8.61 (d, J = 8.2 Hz, Exampletrifluoro-4-((3-(2-(((1r,4r)-4-((2- 1H), 8.42 (d, J = 6.5 Hz, 1H),8.38-8.36 38 methoxyethyl)(methyl)amino)cy- (m, 1H), 7.70 (d, J = 6.5Hz, 1H), 7.60- clohexyl)amino)pyrimidin- 7.54 (m, 2H), 7.43-7.40 (m,1H), 7.30- 4-yl)pyridin-2- 7.21 (m, 1H), 7.15-7.09 (m, 2H), 4.56yl)oxy)phenyl)methanesulfonamide (s, 2H), 4.21-4.11 (m, 1H), 3.78-3.69hydrochloride (m, 2H), 3.53 (d, J = 5.6 Hz, 1H), 3.45 (s, 3H), 3.25-3.20(m, 2H), 2.90 (s, 3H), 2.33 (d, J = 12.3 Hz, 2H), 2.20-2.17 (m, 2H),1.85-1.79 (m, 2H), 1.72-1.58 (m, 2H) 342 1-phenyl-N-(2,3,6-trifluoro-617.3 (300 MHz, CD₃OD) δ 8.63-8.55 (m, Example 4-((3-(2-((5-(1- 1H),8.52 (d, J = 5.7 Hz, 1H), 8.30 (dd, J = 108 fluoroethyl)piperidin-3-4.8, 1.9 Hz, 1H), 7.62 (d, J = 5.7 Hz, yl)amino)pyrimidin-4- 1H),7.56-7.49 (m, 2H), 7.45-7.34 (m, yl)pyridin-2- 4H), 7.27-7.15 (m, 1H),4.73 (t, J = 6.3 yl)oxy)phenyl)methanesulfonamide Hz, 1H), 4.60-4.49 (m,3H), 3.80 (d, J = hydrochloride 13.0 Hz, 1H), 3.55 (d, J = 9.7 Hz, 1H),3.30-3.22 (m, 1H), 3.12-2.98 (m, 1H), 2.59-2.37 (m, 1H), 2.19-1.83 (m,2H), 1.45 (dd, J = 24.7, 6.3 Hz, 3H) 343 1-phenyl-N-(2,3,6-trifluoro-617.3 (300 MHz, CD₃OD) δ 8.71 (s, 1H), 8.48 Example 4-((3-(2-((5-(1- (d,J = 6.0 Hz, 1H), 8.32 (d, J = 4.7 Hz, 108 fluoroethyl)piperidin-3- 1H),7.68 (s, 1H), 7.57-7.49 (m, 2H), yl)amino)pyrimidin-4- 7.46-7.36 (m,4H), 7.31-7.19 (m, 1H), yl)pyridin-2- 4.85-4.62 (m, 2H), 4.56 (s, 2H),3.77 (d, yl)oxy)phenyl)methanesulfonamide J = 11.8 Hz, 1H), 3.47 (d, J =11.5 Hz, hydrochloride 1H), 3.11-2.84 (m, 2H), 2.57-2.09 (m, 2H),1.82-1.59 (m, 1H), 1.41 (dd, J = 24.5, 6.4 Hz, 3H) 3441-phenyl-N-(2,3,6-trifluoro- 617.3 (300 MHz, CD₃OD) δ 8.70 (s, 1H), 8.48Example 4-((3-(2-((5-(1- (d, J = 5.9 Hz, 1H), 8.31 (s, 1H), 7.68 (s, 108fluoroethyl)piperidin-3- 1H), 7.60-7.48 (m, 2H), 7.47-7.35 (m,yl)amino)pyrimidin-4- 4H), 7.32-7.17 (m, 1H), 4.77-4.67 (m,yl)pyridin-2- 1H), 4.56 (s, 3H), 3.85-3.51 (m, 2H),yl)oxy)phenyl)methanesulfonamide 2.89 (t, J = 12.2 Hz, 2H), 2.25 (d, J =12.6 hydrochloride Hz, 2H), 1.65 (d, J = 12.8 Hz, 1H), 1.43 (dd, J =24.6, 6.3 Hz, 3H) 345 1-phenyl-N-(2,3,6-trifluoro- 617.3 (300 MHz,CD₃OD) δ 8.69 (s, 1H), 8.48 Example 4-((3-(2-((5-(1- (d, J = 5.9 Hz,1H), 8.32 (d, J = 4.8 Hz, 108 fluoroethyl)piperidin-3- 1H), 7.67 (s,1H), 7.58-7.47 (m, 2H), yl)amino)pyrimidin-4- 7.47-7.35 (m, 4H),7.29-7.18 (m, 1H), yl)pyridin-2- 4.78-4.67 (m, 1H), 4.56 (s, 3H), 3.89-yl)oxy)phenyl)methanesulfonamide 3.46 (m, 2H), 2.88 (t, J = 12.1 Hz,2H), hydrochloride 2.25 (d, J = 12.6 Hz, 2H), 1.67 (t, J = 12.5 Hz, 1H),1.43 (dd, J = 24.6, 6.3 Hz, 3H) 346 1-phenyl-N-(2,3,6-trifluoro- 617.1(300 MHz, CD₃OD) δ 8.56 (dd, J = 7.6, Example 4-((3-(2-((5-(1- 1.9 Hz,1H), 8.50 (d, J = 5.6 Hz, 1H), 108 fluoroethyl)piperidin-3- 8.28 (dd, J= 4.9, 1.9 Hz, 1H), 7.61-7.49 yl)amino)pyrimidin-4- (m, 3H), 7.46-7.35(m, 4H), 7.30-7.12 yl)pyridin-2- (m, 1H), 4.88-4.65 (m, 1H), 4.58-4.50yl)oxy)phenyl)methanesulfonamide (m, 3H), 3.82 (d, J = 12.9 Hz, 1H),3.46- 3.20 (m, 2H), 3.07 (t, J = 12.0 Hz, 1H), 2.50 (s, 1H), 2.25 (d, J= 14.3 Hz, 1H), 2.07-1.91 (m, 1H), 1.51-1.35 (m, 3H) 3471-phenyl-N-(2,3,6-trifluoro- 617.3 (300 MHz, CD₃OD) δ 8.71 (s, 1H), 8.48Example 4-((3-(2-((5-(1- (d, J = 6.0 Hz, 1H), 8.32 (d, J = 4.7 Hz, 108fluoroethyl)piperidin-3- 1H), 7.68 (s, 1H), 7.56-7.50 (m, 2H),yl)amino)pyrimidin-4- 7.45-7.38 (m, 4H), 7.33-7.20 (m, 1H),yl)pyridin-2- 4.86-4.63 (m, 2H), 4.56 (s, 2H), 3.76 (d,yl)oxy)phenyl)methanesulfonamide J = 12.7 Hz, 1H), 3.47 (d, J = 12.1 Hz,1H), 3.06-2.79 (m, 2H), 2.52-2.08 (m, 2H), 1.66 (d, J = 12.1 Hz, 1H),1.41 (dd, J = 24.4, 6.3 Hz, 3H) 348 1-phenyl-N-(2,3,6-trifluoro- 617.3(300 MHz, CD₃OD) δ 8.51 (dd, J = 7.6, Example 4-((3-(2-((5-(1- 1.9 Hz,1H), 8.41 (d, J = 5.2 Hz, 1H), 108 fluoroethyl)piperidin-3- 8.21 (dd, J= 4.8, 2.0 Hz, 1H), 7.51 (dd, J = yl)amino)pyrimidin-4- 7.4, 2.2 Hz,2H), 7.46-7.28 (m, 5H), yl)pyridin-2- 7.07 (t, J = 9.7 Hz, 1H),4.72-4.59 (m, yl)oxy)phenyl)methanesulfonamide 1H), 4.54-4.43 (m, 2H),4.28 (s, 1H), 3.40-3.21 (m, 2H), 2.99 (dd, J = 12.9, 2.9 Hz, 1H), 2.72(dd, J = 12.7, 10.2 Hz, 1H), 2.29-1.87 (m, 2H), 1.87-1.65 (m, 2H), 1.36(dd, J = 24.6, 6.3 Hz, 3H) 349 N-(2,3,6-trifluoro-4-((3-(2- 649.3 (300MHz, CD₃OD) δ 8.44-8.42 (m, Example (((1r,4r)-4-((2- 1H), 8.32 (d, J =5.2 Hz, 1H), 8.18-8.15 115 methoxyethyl)(methyl)amino)cy- (m, 1H),7.32-7.30 (m, 1H), 7.23 (d, J = clohexyl)amino)pyrimidin- 5.2 Hz, 1H),7.12-7.03 (m, 1H), 3.90- 4-yl)pyridin-2- 3.81 (m, 1H), 3.56 (t, J = 5.6Hz, 2H), yl)oxy)phenyl)cyclohexanesulfonamide 3.37 (s, 3H), 3.09-3.03(m, 1H), 2.86 (t, J = 5.6 Hz, 2H), 2.76-2.71 (m, 1H), 2.46 (s, 3H), 2.32(d, J = 12.5 Hz, 2H), 2.20 (d, J = 12.3 Hz, 2H), 2.01-1.94 (m, 4H), 1.73(d, J = 11.6 Hz, 1H), 1.57-1.54 (m, 4H), 1.44-1.27 (m, 5H) 3501-phenyl-N-(2,3,6-trifluoro- 617.3 (300 MHz, CD₃OD) δ 8.61 (d, J = 7.6Hz, Example 4-((3-(2-((5-(1- 1H), 8.53 (d, J = 5.8 Hz, 1H), 8.31 (d, J =108 fluoroethyl)piperidin-3- 4.8 Hz, 1H), 7.66 (s, 1H), 7.55-7.47 (m,yl)amino)pyrimidin-4- 2H), 7.45-7.36 (m, 4H), 7.23 (t, J = 7.8yl)pyridin-2- Hz, 1H), 4.74-4.60 (m, 2H), 4.56 (s,yl)oxy)phenyl)methanesulfonamide 2H), 3.78 (d, J = 13.3 Hz, 1H), 3.48-3.22 (m, 2H), 3.08 (t, J = 11.8 Hz, 1H), 2.58-2.41 (m, 1H), 2.34-2.17(m, 1H), 2.11-1.91 (m, 1H), 1.62-1.36 (m, 3H) 3511-(2,4-difluorophenyl)-N- 625.2 (400 MHz, DMSO-d₆, 360K) δ 8.46- Example[2,3,6-trifluoro-4-[[3-[2- 8.40 (m, 1H), 8.40-8.36 (m, 1H), 8.27- 40[[(3S,5S)-5-fluoro-3- 8.19 (m, 1H), 7.62-7.53 (m, 1H), 7.35piperidyl]amino]pyrimidin- (dd, J = 7.6, 4.9 Hz, 1H), 7.32-7.11 (m,4-yl]-2- 3H), 7.11-7.03 (m, 1H), 6.90-6.83 (m,pyridyl]oxy]phenyl]methane 1H), 4.92-4.73 (m, 1H), 4.48 (s, 2H),sulfonamide 4.27-4.16 (m, 1H), 2.88-2.73 (m, 2H), 2.61-2.51 (m, 1H),2.22-2.11 (m, 1H), 2.00-1.79 (m, 1H). 352 1-(2-chlorophenyl)-N-[2,3,6-623.2 (400 MHz, DMSO-d₆, 360K) δ 8.42 (d, J = Exampletrifluoro-4-[[3-[2-[[(3S,5S)- 5.1 Hz, 1H), 8.27 (dd, J = 5.0, 2.0 Hz, 405-fluoro-3- 1H), 7.63-7.55 (m, 1H), 7.54-7.45 (m,piperidyl]amino]pyrimidin- 1H), 7.43-7.33 (m, 5H), 7.32-7.26 (m,4-yl]-2- 1H), 4.96 (d, J = 47.1 Hz, 1H), 4.60 (s,pyridyl]oxy]phenyl]methane 2H), 4.35-4.17 (m, 1H), 3.15-2.81 (m,sulfonamide 2H), 2.63-2.54 (m, 1H), 2.46-2.42 (m, 1H), 2.28-2.17 (m,1H), 1.95-1.73 (m, 1H). 353 1-(3-chlorophenyl)-N-[2,3,6- 623.2 (400 MHz,DMSO-d₆) δ 8.58-8.46 (m, Example trifluoro-4-[[3-[2-[[(3S,5S)- 1H), 8.44(d, J = 5.0 Hz, 1H), 8.28 (dd, J = 40 5-fluoro-3- 4.9, 2.0 Hz, 1H),7.50-7.38 (m, 6H), piperidyl]amino]pyrimidin- 7.34-7.28 (m, 1H),5.12-4.95 (m, 1H), 4-yl]-2- 4.51 (s, 2H), 4.41-4.26 (m, 1H), 3.08-pyridyl]oxy]phenyl]methane 2.91 (m, 3H), 2.68-2.59 (m, 1H), 2.31-sulfonamide 2.20 (m, 1H), 2.00-1.74 (m, 1H). 3541-(4-chlorophenyl)-N-[2,3,6- 623.2 (400 MHz, DMSO-d₆) δ 8.42 (d, J = 5.2Example trifluoro-4-[[3-[2-[[(3S,5S)- Hz, 1H), 8.27 (dd, J = 4.8, 2.0Hz, 1H), 40 5-fluoro-3- 7.49-7.34 (m, 7H), 7.31-7.26 (m, 1H),piperidyl]amino]pyrimidin- 5.06-4.87 (m, 1H), 4.46 (s, 2H), 4.33-4-yl]-2- 4.20 (m, 1H), 2.89 (s, 3H), 2.61-2.53pyridyl]oxy]phenyl]methane (m, 1H), 2.47 (d, J = 4.0 Hz, 0H), 2.45-sulfonamide 2.38 (m, 0H), 2.27-2.17 (m, 1H), 1.96- 1.75 (m, 1H). 3551-(2-fluorophenyl)-N-[2,3,6- 607.2 (400 MHz, DMSO-d₆) δ 8.44 (d, J = 5.2Example trifluoro-4-[[3-[2-[[(3S,5S)- Hz, 1H), 8.29 (dd, J = 4.9, 1.9Hz, 1H), 40 5-fluoro-3- 7.56-7.48 (m, 3H), 7.48-7.37 (m, 2H),piperidyl]amino]pyrimidin- 7.35-7.30 (m, 1H), 7.30-7.21 (m, 2H),4-yl]-2- 5.19-5.01 (m, 1H), 4.56 (s, 2H), 4.41-pyridyl]oxy]phenyl]methane 4.33 (m, 1H), 3.17-2.98 (m, 3H), 2.72-sulfonamide 2.65 (m, 1H), 2.35-2.21 (m, 1H), 2.00- 1.73 (m, 1H). 3561-(2-pyridyl)-N-[2,3,6- 590.2 (400 MHz, DMSO-d₆) δ 8.55-8.50 (m, Exampletrifluoro-4-[[3-[2-[[(3S,5S)- 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.30-8.25121 5-fluoro-3- (m, 1H), 7.84-7.75 (m, 1H), 7.60-7.54piperidyl]amino]pyrimidin- (m, 1H), 7.40-7.24 (m, 5H), 5.01-4.794-yl]-2- (m, 1H), 4.51 (s, 2H), 4.23-4.19 (m, pyridyl]oxy]phenyl]methane1H), 3.20-2.95 (m, 3H), 2.90-2.71 (m, sulfonamide 1H), 2.21-2.15 (m,1H), 1.94-1.73 (m, 1H). 357 1-(2-cyano-4-fluoro- 632.1 (400 MHz,DMSO-d₆, 360K) δ 8.43 (dd, J = Example phenyl)-N-[2,3,6-trifluoro-4-7.5, 2.0 Hz, 1H), 8.39 (d, J = 5.1 Hz, 40 [[3-[2-[[(3S,5S)-5-fluoro-3-1H), 8.24 (dd, J = 4.8, 1.9 Hz, 1H), 7.78- piperidyl]amino]pyrimidin-7.72 (m, 2H), 7.60-7.53 (m, 1H), 7.35 4-yl]-2- (dd, J = 7.6, 4.8 Hz,1H), 7.26-7.19 (m, pyridyl]oxy]phenyl]methane 2H), 6.95 (d, J = 7.8 Hz,1H), 4.98-4.81 sulfonamide (m, 1H), 4.59 (s, 2H), 4.31-4.19 (m, 1H),3.20-3.13 (m, 1H), 2.92-2.81 (m, 2H), 2.66-2.56 (m, 1H), 2.26-2.13 (m,1H), 1.98-1.81 (m, 1H). 358 1-(2-cyanophenyl)-N-[2,3,6- 614.2 (400 MHz,DMSO-d₆ 360K) δ 8.45- Example trifluoro-4-[[3-[2-[[(3S,5S)- 8.41 (m,1H), 8.38 (d, J = 5.2 Hz, 1H), 40 5-fluoro-3- 8.26-8.22 (m, 1H), 7.81(d, J = 7.6 Hz, piperidyl]amino]pyrimidin- 1H), 7.75-7.65 (m, 2H),7.57-7.48 (m, 4-yl]-2- 1H), 7.35 (dd, J = 7.5, 4.8 Hz, 1H), 7.27-pyridyl]oxy]phenyl]methane 7.18 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H),sulfonamide 4.97-4.77 (m, 1H), 4.60 (s, 2H), 4.28- 4.19 (m, 1H),2.90-2.76 (m, 3H), 2.62- 2.55 (m, 1H), 2.24-2.13 (m, 1H), 1.98- 1.79 (m,1H). 359 1-(4-pyridyl)-N-[2,3,6- 590.2 NO NMR Exampletrifluoro-4-[[3-[2-[[(3S,5S)- 40 5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2- pyridyl]oxy]phenyl]methane sulfonamide 360 1-(4-cyano-2-fluoro-632.2 (400 MHz, DMSO-d₆ 360K) δ 8.42 (dd, J = Examplephenyl)-N-[2,3,6-trifluoro-4- 7.5, 2.0 Hz, 1H), 8.38 (d, J = 5.1 Hz, 125[[3-[2-[[(3S,5S)-5-fluoro-3- 1H), 8.24 (dd, J = 4.8, 2.0 Hz, 1H), 7.80-piperidyl]amino]pyrimidin- 7.70 (m, 2H), 7.70-7.63 (m, 1H), 7.354-yl]-2- (dd, J = 7.6, 4.8 Hz, 1H), 7.28-7.20 (m,pyridyl]oxy]phenyl]methane 2H), 6.94-6.87 (m, 1H), 4.98-4.81 (m,sulfonamide 1H), 4.56 (s, 2H), 4.32-4.21 (m, 1H), 3.22-3.11 (m, 1H),2.97-2.79 (m, 2H), 2.67-2.57 (m, 1H), 2.22-2.18 (m, 1H), 2.00-1.80 (m,1H). 361 3-fluoro-4-[[2,3,6-trifluoro- 650.2 ¹H NMR (400 MHz, DMSO-d₆,360K) δ Example 4-[[3-[2-[[(3S,5S)-5-fluoro-3- 8.43 (dd, J = 7.5, 2.0Hz, 1H), 8.38 (d, J = 40 piperidyl]amino]pyrimidin- 5.1 Hz, 1H), 8.24(dd, J = 4.8, 1.9 Hz, 4-yl]-2- 1H), 7.74-7.65 (m, 2H), 7.64-7.56 (m,pyridyl]oxy]phenyl]sulfam- 1H), 7.36 (dd, J = 7.5, 4.8 Hz, 1H), 7.33-oylmethyl]benzamide 7.25 (m, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.91 (d, J =8.0 Hz, 1H), 4.95-4.75 (m, 1H), 4.54 (s, 2H), 4.29-4.16 (m, 1H),2.91-2.74 (m, 3H), 2.62-2.52 (m, 1H), 2.23-2.11 (m, 1H), 1.99-1.78 (m,1H). 362 1-(4-chloro-2-cyano- 648.1 (400 MHz, DMSO-d₆, 360K) δ 8.42 (dd,J = Example phenyl)-N-[2,3,6-trifluoro-4- 2.7, 2.0 Hz, 1H), 8.39 (d, J =5.2 Hz, 40 [[3-[2-[[(3S,5S)-5-fluoro-3- 1H), 8.24 (dd, J = 4.8, 2.0 Hz,1H), 7.94 piperidyl]amino]pyrimidin- (d, J = 2.2 Hz, 1H), 7.78-7.69 (m,2H), 4-yl]-2- 7.34 (dd, J = 2.5, 4.8 Hz, 1H), 7.25 (d, J =pyridyl]oxy]phenyl]methane 5.1 Hz, 1H), 7.23-7.16 (m, 1H), 6.95 (d,sulfonamide J = 8.0 Hz, 1H), 4.98-4.80 (m, 1H), 4.56 (s, 2H), 4.31-4.21(m, 1H), 3.20-3.13 (m, 1H), 2.87-2.81 (m, 2H), 2.65-2.57 (m, 1H),2.25-2.14 (m, 1H), 1.98-1.81 (m, 1H). 363 1-(2,6-difluorophenyl)-N-625.2 (400 MHz, DMSO-d₆, 360K) δ 8.43 (dd, J = Example[2,3,6-trifluoro-4-[[3-[2- 7.5, 2.0 Hz, 1H), 8.38 (d, J = 5.0 Hz, 40[[(3S,5S)-5-fluoro-3- 1H), 8.24 (dd, J = 4.9, 1.9 Hz, 1H), 7.49-piperidyl]amino]pyrimidin- 7.41 (m, 1H), 7.38-7.32 (m, 1H), 7.32-4-yl]-2- 7.25 (m, 1H), 7.25-7.20 (m, 1H), 7.13-pyridyl]oxy]phenyl]methane 7.06 (m, 2H), 6.93-6.86 (m, 1H), 4.93-sulfonamide 4.76 (m, 1H), 4.54 (s, 2H), 4.29-4.15 (m, 1H), 2.90-2.74 (m,3H), 2.57 (ddd, J = 12.5, 9.1, 1.9 Hz, 1H), 2.21-2.12 (m, 1H), 1.98-1.80(m, 1H). 364 1-(4-chloro-2-fluoro- 641.1 (400 MHz, DMSO-d₆, 360K) δ8.45- Example phenyl)-N-[2,3,6-trifluoro-4- 8.40 (m, 1H), 8.38 (d, J =5.1 Hz, 1H), 129 [[3-[2-[[(3S,5S)-5-fluoro-3- 8.26-8.21 (m, 1H),7.60-7.52 (m, 1H), piperidyl]amino]pyrimidin- 7.40-7.31 (m, 2H),7.31-7.20 (m, 3H), 4-yl]-2- 6.90-6.83 (m, 1H), 4.92-4.75 (m, 1H),pyridyl]oxy]phenyl]methane 4.46 (s, 2H), 4.27-4.17 (m, 1H), 2.81-sulfonamide 2.73 (m, 2H), 2.61-2.53 (m, 2H), 2.22- 2.11 (m, 1H),1.98-1.80 (m, 1H). 365 1-(2-chloro-4-fluoro- 641.1 (400 MHz, DMSO-d₆,360K) δ 8.46- Example phenyl)-N-[2,3,6-trifluoro-4- 8.40 (m, 1H),8.40-8.35 (m, 1H), 8.26- 129 [[3-[2-[[(3S,5S)-5-fluoro-3- 8.21 (m, 1H),7.65 (dd, J = 8.8, 6.3 Hz, piperidyl]amino]pyrimidin- 1H), 7.44-7.32 (m,2H), 7.32-7.17 (m, 4-yl]-2- 3H), 6.87 (d, J = 8.0 Hz, 1H), 4.92-4.73pyridyl]oxy]phenyl]methane (m, 1H), 4.62 (s, 2H), 4.27-4.17 (m,sulfonamide 1H), 2.90-2.74 (m, 3H), 2.61-2.51 (m, 1H), 2.22-2.10 (m,1H), 1.98-1.79 (m, 1H). 366 1-(3-chloro-4-fluoro- 641.1 (400 MHz,DMSO-d₆, 360K) δ 8.42 (dd, J = Example phenyl)-N-[2,3,6-trifluoro-4-7.5, 2.0 Hz, 1H), 8.37 (d, J = 5.1 Hz, 129 [[3-[2-[[(3S,5S)-5-fluoro-3-1H), 8.23 (dd, J = 4.8, 2.0 Hz, 1H), 7.63 piperidyl]amino]pyrimidin-(dd, J = 7.3, 2.2 Hz, 1H), 7.47-7.40 (m, 4-yl]-2- 1H), 7.38-7.32 (m,2H), 7.27-7.19 (m, pyridyl]oxy]phenyl]methane 2H), 6.87-6.80 (m, 1H),6.03 (s, 1H), sulfonamide 4.90-4.73 (m, 1H), 4.44 (s, 2H), 4.25- 4.16(m, 1H), 3.13-3.05 (m, 2H), 2.89- 2.72 (m, 1H), 2.59-2.51 (m, 1H), 2.20-2.11 (m, 1H), 1.98-1.80 (m, 1H). 367 1-(2-chloro-6-fluorophenyl)- 641.1(400 MHz, DMSO-d₆, 360K) δ 8.43 (dd, J = ExampleN-(2,3,6-trifluoro-4-((3-(2- 7.6, 1.9 Hz, 1H), 8.38 (d, J = 5.1 Hz, 129(((3S,5S)-5-fluoropiperidin- 1H), 8.24 (dd, J = 4.8, 1.9 Hz, 1H), 7.44-3-yl)amino)pyrimidin-4- 7.17 (m, 6H), 6.84 (d, J = 7.9 Hz, 1H),yl)pyridin-2- 4.91-4.74 (m, 1H), 4.71-4.66 (m, 2H),yl)oxy)phenyl)methanesulfonamide 4.27-4.15 (m, 1H), 3.14-3.06 (m, 1H),2.86-2.73 (m, 2H), 2.60-2.52 (m, 1H), 2.23-2.10 (m, 1H), 1.99-1.80 (m,1H). 368 N-(2,3,6-trifluoro-4-((3-(2- 581.2 (400 MHz, DMSO-d₆, 360K) δ8.39 (dd, J = Example (((3S,5S)-5-fluoropiperidin- 23.5, 6.4 Hz, 2H),8.23 (d, J = 4.8 Hz, 129 3-yl)amino)pyrimidin-4- 1H), 7.39-7.25 (m, 2H),7.20 (d, J = 5.1 yl)pyridin-2- Hz, 1H), 6.84-6.77 (m, 1H), 4.86-4.68yl)oxy)phenyl)cyclohexanesulfonamide (m, 1H), 4.20-4.12 (m, 1H),2.88-2.63 (m, 5H), 2.23-2.08 (m, 3H), 1.95-1.79 (m, 3H), 1.69-1.61 (m,1H), 1.55-1.42 (m, 2H), 1.36-1.15 (m, 3H). 369N-(2,3,6-trifluoro-4-((3-(2- 567.2 (400 MHz, DMSO-d₆, 360K) δ 8.39 (dd,,Example (((3S,5S)-5-fluoropiperidin- J = 22.4, 6.4 Hz, 2H), 8.23 (d, J =4.9 Hz, 129 3-yl)amino)pyrimidin-4- 1H), 7.38-7.31 (m, 1H), 7.29-7.15(m, yl)pyridin-2- 2H), 6.80 (d, J = 8.1 Hz, 1H), 4.85-4.67yl)oxy)phenyl)cyclopentanesulfonamide (m, 1H), 4.22-4.12 (m, 1H),3.63-3.54 (m, 1H), 2.86-2.67 (m, 3H), 2.18-2.07 (m, 1H), 2.05-1.92 (m,5H), 1.90-1.78 (m, 1H), 1.75-1.56 (m, 4H). 370N-(2,3,6-trifluoro-4-((3-(2- 657.2 (400 MHz, DMSO-d₆, 360K) δ 8.43 (d, J= Example (((3S,5S)-5-fluoropiperidin- 7.5 Hz, 1H), 8.38 (d, J = 5.1 Hz,1H), 129 3-yl)amino)pyrimidin-4- 8.24 (d, J = 4.9 Hz, 1H), 7.74-7.64 (m,yl)pyridin-2-yl)oxy)phenyl)-1-(4- 4H), 7.40-7.33 (m, 1H), 7.33-7.25 (m,(trifluoromethyl)phenyl)methanesulfonamide 1H), 7.22 (d, J = 5.1 Hz,1H), 6.88 (d, J = 8.0 Hz, 1H), 4.93-4.76 (m, 1H), 4.57 (s, 2H),4.27-4.17 (m, 1H), 2.85-2.74 (m, 3H), 2.61-2.54 (m, 1H), 2.21-2.13 (m,1H), 1.97-1.81 (m, 1H). 371 1-(4-(difluoromethyl)phenyl)-N- 639.2 (400MHz, DMSO-d₆, 360K) δ 8.43 (d, J = Example (2,3,6-trifluoro-4-((3-(2-7.4 Hz, 1H), 8.38 (d, J = 5.1 Hz, 1H), 129 (((3S,5S)-5-fluoropiperidin-8.27-8.21 (m, 1H), 7.62-7.52 (m, 4H), 3-yl)amino)pyrimidin-4- 7.36 (dd,J = 7.5, 4.8 Hz, 1H), 7.32-7.25 yl)pyridin-2- (m, 1H), 7.22 (d, J = 5.1Hz, 1H), 6.88- yl)oxy)phenyl)methanesulfonamide 6.82 (m, 1H), 4.90-4.74(m, 1H), 4.52 (s, 2H), 4.25-4.16 (m, 1H), 2.83-2.72 (m, 3H), 2.60-2.53(m, 1H), 2.14 (d, J = 11.4 Hz, 1H), 1.96-1.82 (m, 1H). 3721-(4-fluorophenyl)-N-(2,3,6- 607.2 (400 MHz, DMSO-d₆, 360K) δ 8.42 (d, J= Example trifluoro-4-((3-(2-(((3S,5S)- 7.5, 1.9 Hz, 1H), 8.37 (d, J =5.3, 1.7 129 5-fluoropiperidin-3- Hz, 1H), 8.23 (dd, J = 4.7, 2.0 Hz,1H), yl)amino)pyrimidin-4- 7.51-7.43 (m, 2H), 7.39-7.31 (m, 1H),yl)pyridin-2- 7.29-7.19 (m, 2H), 7.19-7.10 (m, 2H),yl)oxy)phenyl)methanesulfonamide 6.83 (d, J = 7.8 Hz, 1H), 4.89-4.71 (m,1H), 4.42 (s, 2H), 4.24-4.13 (m, 1H), 2.87-2.70 (m, 3H), 2.58-2.51 (m,1H), 2.20-2.09 (m, 1H), 1.96-1.81 (m, 1H). 373N-(2,3,6-trifluoro-4-((3-(2- 657.2 (400 MHz, DMSO-d₆, 360K) δ 8.43 (dd,J = Example (((3S,5S)-5-fluoropiperidin- 7.5, 1.9 Hz, 1H), 8.38 (d, J =5.2 Hz, 129 3-yl)amino)pyrimidin-4- 1H), 8.24 (dd, J = 4.8, 1.9 Hz, 1H),7.82 yl)pyridin-2-yl)oxy)phenyl)- (d, J = 7.8 Hz, 1H), 7.74 (dd, J =7.8, 1.4 1-(2- Hz, 1H), 7.71-7.63 (m, 1H), 7.59-7.51(trifluoromethyl)phenyl)methanesulfonamide (m, 1H), 7.35 (dd, J = 7.6,4.9 Hz, 1H), 7.33-7.23 (m, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.90 (d, J =8.0 Hz, 1H), 4.94-4.74 (m, 1H), 4.66 (s, 2H), 4.28-4.16 (m, 1H),3.14-3.07 (m, 1H), 2.97-2.74 (m, 2H), 2.62-2.51 (m, 1H), 2.22-2.12 (m,1H), 1.99-1.78 (m, 1H). 374 N-(2,3,6-trifluoro-4-((3-(2- 657.2 (400 MHz,DMSO-d₆, 360K) δ 8.43 (dd, J = Example (((3S,5S)-5-fluoropiperidin- 7.6,1.9 Hz, 1H), 8.38 (d, J = 5.1 Hz, 129 3-yl)amino)pyrimidin-4- 1H), 8.24(dd, J = 4.8, 1.9 Hz, 1H), 7.82- yl)pyridin-2-yl)oxy)phenyl)- 7.77 (m,1H), 7.77-7.71 (m, 1H), 7.71- 1-(3- 7.64 (m, 1H), 7.64-7.56 (m, 1H),7.35 (trifluoromethyl)phenyl)methanesulfonamide (dd, J = 7.6, 4.9 Hz,1H), 7.31-7.21 (m, 1H), 7.22 (d, J = 5.1 Hz, 1H), 6.89 (d, J = 8.0 Hz,1H), 4.93-4.73 (m, 1H), 4.56 (s, 2H), 4.28-4.14 (m, 1H), 3.14-3.05 (m,1H), 2.96-2.73 (m, 2H), 2.61-2.50 (m, 1H), 2.23-2.10 (m, 1H), 1.99-1.78(m, 1H). 375 1-p-tolyl-N-(2,3,6-trifluoro- 603.2 (400 MHz, DMSO-d₆,360K) δ 8.43 (dd, J = Example 4-((3-(2-(((3S,5S)-5- 7.5, 1.9 Hz, 1H),8.38 (d, J = 5.1 Hz, 129 fluoropiperidin-3- 1H), 8.24 (dd, J = 4.9, 2.0Hz, 1H), 7.36 yl)amino)pyrimidin-4- (dd, J = 7.5, 4.8 Hz, 1H), 7.34-7.29(m, yl)pyridin-2- 3H), 7.22 (d, J = 5.1 Hz, 1H), 7.20-7.15yl)oxy)phenyl)methanesulfonamide (m, 2H), 6.86 (d, J = 8.0 Hz, 1H),4.91- 4.70 (m, 1H), 4.42 (s, 2H), 4.27-4.12 (m, 1H), 3.09-3.08 (m, 1H),2.95-2.86 (m, 1H), 2.86-2.71 (m, 1H), 2.57-2.51 (m, 1H), 2.31 (s, 3H),2.21-2.08 (m, 1H), 1.97-1.79 (m, 1H). 376 1-(bicyclo[2.2.1]heptan-1-607.2 (400 MHz, DMSO-d₆, 360K) δ 8.43 (dd, J = Exampleyl)-N-(2,3,6-trifluoro-4-((3- 7.5, 2.0 Hz, 1H), 8.37 (d, J = 5.1 Hz, 129(2-(((3S,5S)-5- 1H), 8.23 (dd, J = 4.7, 1.9 Hz, 1H), 7.35fluoropiperidin-3- (ddd, J = 10.9, 7.1, 3.5 Hz, 2H), 7.21 (d, J =yl)amino)pyrimidin-4- 5.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H),yl)pyridin-2- 4.89-4.71 (m, 1H), 4.25-4.12 (m, 1H),yl)oxy)phenyl)methanesulfonamide 3.51 (s, 2H), 2.93-2.71 (m, 3H), 2.58-2.51 (m, 1H), 2.22-2.09 (m, 2H), 1.96- 1.79 (m, 1H), 1.69-1.54 (m, 4H),1.54- 1.45 (m, 2H), 1.40 (s, 2H), 1.32-1.24 (m, 2H). 3771-(bicyclo[2.2.2]octan-1-yl)- 621.3 (400 MHz, DMSO-d₆, 360K) δ 8.43 (dd,J = Example N-(2,3,6-trifluoro-4-((3-(2- 7.5, 2.0 Hz, 1H), 8.37 (d, J =5.1 Hz, 129 (((3S,5S)-5-fluoropiperidin- 1H), 8.23 (dd, J = 4.8, 2.0 Hz,1H), 7.40- 3-yl)amino)pyrimidin-4- 7.29 (m, 2H), 7.20 (d, J = 5.2 Hz,1H), yl)pyridin-2- 6.86 (d, J = 8.0 Hz, 1H), 4.90-4.71 (m,yl)oxy)phenyl)methanesulfonamide 1H), 4.25-4.12 (m, 1H), 3.10-3.06 (m,2H), 2.96-2.86 (m, 3H), 2.84-2.71 (m, 1H), 2.56-2.51 (m, 1H), 2.21-2.08(m, 1H), 1.97-1.77 (m, 1H), 1.67-1.51 (m, 12H). 3781-(2,5-difluorophenyl)-N- 625.1 (400 MHz, DMSO-d₆, 360K) δ 8.42 (dd, J =Example (2,3,6-trifluoro-4-((3-(2- 7.5, 2.0 Hz, 1H), 8.38 (d, J = 5.1Hz, 129 (((3S,5S)-5-fluoropiperidin- 1H), 8.24 (dd, J = 4.8, 2.0 Hz,1H), 7.39- 3-yl)amino)pyrimidin-4- 7.32 (m, 2H), 7.26-7.14 (m, 4H), 6.88yl)pyridin-2- (d, J = 7.9 Hz, 1H), 4.93-4.74 (m, 1H),yl)oxy)phenyl)methanesulfonamide 4.42 (s, 2H), 4.27-4.15 (m, 1H), 2.87-2.74 (m, 3H), 2.55 (ddd, J = 12.5, 8.9, 1.9 Hz, 1H), 2.22-2.11 (m, 1H),1.97-1.80 (m, 1H). 379 1-(4-cyanophenyl)-N-(2,3- 592.2 (400 MHz,DMSO-d₆, 360K) δ 8.43- Example difluoro-4-((3-(2-(((S)- 8.34 (m, 2H),8.21 (dd, J = 4.8, 2.0 Hz, 144 piperidin-3- 1H), 7.73-7.67 (m, 2H),7.62-7.56 (m, yl)amino)pyrimidin-4- 2H), 7.32-7.21 (m, 2H), 7.16-7.06(m, yl)pyridin-2- 1H), 6.87 (td, J = 7.4, 6.5, 2.1 Hz, 2H),yl)oxy)phenyl)ethane-1- 4.42 (q, J = 7.0 Hz, 1H), 4.07-3.95 (m,sulfonamide 1H), 3.25-3.21 (m, 1H), 2.94-2.92 (m, 1H), 2.70-2.63 (m,2H), 1.99-1.91 (m, 1H), 1.82-1.71 (m, 1H), 1.66 (d, J = 7.0 Hz, 3H),1.63-1.52 (m, 2H). 380 (S)-N-(2,3-difluoro-4-((3-(2- 583.2 (400 MHz,DMSO-d₆) δ 8.41 (d, J = 5.1 Example (piperidin-3- Hz, 1H), 8.22 (dd, J =4.8, 2.0 Hz, 1H), 144 ylamino)pyrimidin-4- 7.38-7.18 (m, 6H), 7.02-6.86(m, 3H), yl)pyridin-2-yl)oxy)phenyl)-1-(2- 4.28 (s, 2H), 4.07-3.95 (m,1H), 3.68 (s, methoxyphenyl)methanesulfonamide 3H), 3.21-3.18 (m, 1H),3.02-2.92 (m, 1H), 2.68-2.53 (m, 2H), 1.98-1.91 (m, 1H), 1.81-1.72 (m,1H), 1.60-1.49 (m, 2H). 381 (S)-N-(2,3-difluoro-4-((3-(2- 627.2 (400MHz, DMSO-d₆, 360K) δ 8.49- Example (piperidin-3- 8.28 (m, 2H), 8.18(dd, J = 4.6, 2.2 Hz, 144 ylamino)pyrimidin-4- 1H), 7.92 (d, J = 7.6 Hz,2H), 7.76 (d, J = yl)pyridin-2-yl)oxy)phenyl)- 7.5 Hz, 2H), 7.40-7.20(m, 7H), 6.76- 9H-fluorene-9-sulfonamide 6.67 (m, 1H), 6.67-6.60 (m,1H), 5.23 (s, 1H), 3.93-3.79 (m, 1H), 2.67-2.64 (m, 1H), 2.34-2.29 (m,1H), 2.07-1.87 (m, 3H), 1.70-1.36 (m, 3H). 382 N-(4-((3-(2-(((1r,4r)-4-619.2 (400 MHz, DMSO-d₆) δ 8.40-8.32 (m, Example(dimethylamino)cyclohexyl) 2H), 8.26 (dd, J = 4.8, 2.0 Hz, 1H), 7.34 125amino)pyrimidin-4- (dd, J = 7.6, 4.9 Hz, 1H), 7.24 (d, J = 7.8 step 1;yl)pyridin-2-yl)oxy)-2,3,6- Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.13-Example trifluorophenyl)-3,3,3- 7.03 (m, 1H), 3.78-3.67 (m, 1H),3.02-2.86 (m, 3H), 129 trifluoropropane-1- 2.73-2.58 (m, 7H), 2.13-2.02(m, 2H), 1.99-1.92 step 1 sulfonamide (m, 2H), 1.56-1.19 (m, 4H). 3831-m-tolyl-N-(2,3,6-trifluoro- 603.2 (400 MHz, DMSO-d₆, 360K) δ 8.46 (dd,J = Example 4-((3-(2-(((3S,5S)-5- 7.6, 2.0 Hz, 1H), 8.42 (d, J = 5.1 Hz,129 fluoropiperidin-3- 1H), 8.26 (dd, J = 4.8, 1.9 Hz, 1H), 7.43-yl)amino)pyrimidin-4- 7.33 (m, 2H), 7.32-7.13 (m, 6H), 5.20-yl)pyridin-2- 5.02 (m, 1H), 4.45-4.37 (m, 1H), 3.41-yl)oxy)phenyl)methanesulfonamide 3.29 (m, 2H), 3.21-3.11 (m, 1H), 2.84-2.75 (m, 1H), 2.36-2.27 (m, 4H), 2.03- 1.84 (m, 1H), 1.32-1.26 (m, 1H),0.93- 0.79 (m, 1H). 384 1-(2-fluoro-4- 621.2 (400 MHz, DMSO-d₆, 360K) δ8.43 (dd, J = Example methylphenyl)-N-(2,3,6- 7.6, 2.0 Hz, 1H), 8.38 (d,J = 5.0 Hz, 129 trifluoro-4-((3-(2-(((3S,5S)- 1H), 8.24 (dd, J = 4.9,2.0 Hz, 1H), 7.42- 5-fluoropiperidin-3- 7.27 (m, 3H), 7.22 (d, J = 5.1Hz, 1H), yl)amino)pyrimidin-4- 7.05-7.00 (m, 2H), 6.88 (d, J = 8.0 Hz,yl)pyridin-2- 1H), 4.91-4.73 (m, 1H), 4.47 (s, 2H),yl)oxy)phenyl)methanesulfonamide 4.26-4.15 (m, 1H), 2.89-2.74 (m, 3H),2.59-2.51 (m, 1H), 2.33 (s, 3H), 2.20- 2.11 (m, 1H), 1.97-1.79 (m, 1H).385 1-(3-methoxyphenyl)-N- 619.2 (400 MHz, DMSO-d₆, 360K) δ 8.43 (dd, J= Example (2,3,6-trifluoro-4-((3-(2- 7.6, 2.0 Hz, 1H), 8.38 (d, J = 5.1Hz, 129 (((3S,5S)-5-fluoropiperidin- 1H), 8.24 (dd, J = 4.9, 2.0 Hz,1H), 7.38- 3-yl)amino)pyrimidin-4- 7.25 (m, 3H), 7.22 (d, J = 5.1 Hz,1H), yl)pyridin-2- 7.04-7.00 (m, 2H), 6.94-6.89 (m, 1H),yl)oxy)phenyl)methanesulfonamide 6.87 (d, J = 8.0 Hz, 1H), 4.89-4.73 (m,1H), 4.44 (s, 2H), 4.24-4.14 (m, 1H), 3.77 (s, 3H), 2.90 (d, J = 4.3 Hz,1H), 2.85-2.79 (m, 1H), 2.79-2.72 (m, 1H), 2.57-2.50 (m, 1H), 2.20-2.10(m, 1H), 1.96-1.80 (m, 1H). 386 1-o-tolyl-N-(2,3,6-trifluoro- 603.2 (400MHz, DMSO-d₆, 360K) δ 8.43 (dd, J = Example 4-((3-(2-(((3S,5S)-5- 7.5,1.9 Hz, 1H), 8.38 (d, J = 5.1 Hz, 129 fluoropiperidin-3- 1H), 8.24 (dd,J = 4.8, 1.9 Hz, 1H), 7.38- yl)amino)pyrimidin-4- 7.30 (m, 3H),7.26-7.15 (m, 4H), 6.87 yl)pyridin-2- (d, J = 8.0 Hz, 1H), 4.89-4.72 (m,1H), yl)oxy)phenyl)methanesulfonamide 4.53 (s, 2H), 4.24-4.14 (m, 1H),2.90- 2.72 (m, 3H), 2.57-2.50 (m, 1H), 2.39 (s, 3H), 2.20-2.10 (m, 1H),1.96-1.80 (m, 1H). 387 (*S)-1-phenyl-N-(2,3,6- 603.2 (400 MHz, DMSO-d₆,360K) δ 8.43 (dd, J = Example trifluoro-4-((3-(2-(((3S,5S)- 7.5, 2.0 Hz,1H), 8.37 (d, J = 5.1 Hz, 99 5-fluoropiperidin-3- 1H), 8.24 (dd, J =4.8, 1.9 Hz, 1H), 7.48- yl)amino)pyrimidin-4- 7.44 (m, 2H), 7.38-7.25(m, 5H), 7.21 yl)pyridin-2- (d, J = 5.0 Hz, 1H), 6.85 (d, J = 8.0 Hz,yl)oxy)phenyl)ethane-1- 1H), 4.88-4.71 (m, 1H), 4.44 (q, J = 7.0sulfonamide Hz, 1H), 4.23-4.13 (m, 1H), 2.89-2.87 (m, 1H), 2.83-2.78 (m,1H), 2.75-2.70 (m, 1H), 2.56-2.51 (m, 1H), 2.20-2.09 (m, 1H), 1.96-1.79(m, 1H), 1.76 (d, J = 7.0 Hz, 3H). 388 (*R)-1-phenyl-N-(2,3,6- 603.2(400 MHz, DMSO-d₆, 360K) δ 8.43 (dd, J = Exampletrifluoro-4-((3-(2-(((3S,5S)- 7.5, 2.0 Hz, 1H), 8.37 (d, J = 5.1 Hz, 995-fluoropiperidin-3- 1H), 8.24 (dd, J = 4.8, 1.9 Hz, 1H), 7.48-yl)amino)pyrimidin-4- 7.44 (m, 2H), 7.38-7.25 (m, 5H), 7.21yl)pyridin-2- (d, J = 5.0 Hz, 1H), 6.85 (d, J = 8.0 Hz,yl)oxy)phenyl)ethane-1- 1H), 4.88-4.71 (m, 1H), 4.44 (q, J = 7.0sulfonamide Hz, 1H), 4.23-4.13 (m, 1H), 2.89-2.87 (m, 1H), 2.83-2.78 (m,1H), 2.75-2.70 (m, 1H), 2.56-2.51 (m, 1H), 2.20-2.09 (m, 1H), 1.96-1.79(m, 1H), 1.76 (d, J = 7.0 Hz, 3H). 389 N-(2,3,6-trifluoro-4-((3-(2-658.2 (400 MHz, DMSO-d₆, 360K) δ 8.68 (d, J = Example(((3S,5S)-5-fluoropiperidin- 4.6 Hz, 1H), 8.43 (dd, J = 7.5, 2.1 Hz, 1293-yl)amino)pyrimidin-4- 1H), 8.39 (d, J = 5.0 Hz, 1H), 8.26-8.20yl)pyridin-2-yl)oxy)phenyl)-1-(2- (m, 2H), 7.74-7.68 (m, 1H), 7.38-7.33(trifluoromethyl)pyridin-3- (m, 1H), 7.27-7.20 (m, 2H), 6.95 (d, J =yl)methanesulfonamide 7.8 Hz, 1H), 4.99-4.82 (m, 1H), 4.65 (s, 2H),4.33-4.20 (m, 1H), 3.21-3.14 (m, 2H), 2.89-2.82 (m, 1H), 2.67-2.57 (m,1H), 2.26-2.15 (m, 1H), 1.99-1.81 (m, 1H). *= arbitrarily assigned

Abbreviations

ACN: acetonitrile

DCM: dichloromethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

EtOAc: ethyl acetate

EtOH: ethanol

h: hour

HCl: hydrochloric acid

HPLC: High-performance liquid chromatography

IPA: isopropyl alcohol

LCMS: Liquid chromatography-mass spectrometry

MeCN: acetonitrile

THF: tetrahydrofuran

Example 1N-[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-methyl-phenyl]-2-chloro-benzenesulfonamidehydrochloride (Compound 101) Step 1: tert-ButylN-[4-[[4-[2-(4-amino-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate

A mixture of tert-butyl(3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate(151 mg, 0.41 mmol), 4-amino-2-methylphenol (50 mg, 0.41 mmol) andcesium carbonate (397 mg, 1.22 mmol) in DMSO (1 mL) was degassed 3 timesand stirred at 130° C. for 1.5 h under N₂. The reaction mixture wascooled to room temperature, diluted with ethyl acetate, washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by prep-HPLC (petroleum ether/ethylacetate=1/1) to give the title compound (110 mg, 55% yield) as a yellowsolid. LCMS (ESI) [M+H]⁺=491.

Step 2: tert-ButylN-[4-[[4-[2-[4-[(2-chlorophenyl)sulfonylamino]-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate

To a solution of tert-butylN-[4-[[4-[2-(4-amino-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate(110 mg, 0.22 mmol) in pyridine (2 mL) was added2-chlorobenzenesulfonylchloride (56 mg, 0.27 mmol) at 0° C. Aftercompletion of the addition, the reaction mixture was stirred at roomtemperature for 4 h. The mixture was concentrated in vacuo, and waterwas added. The mixture was extracted twice with DCM, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (ethyl acetate/:petroleum ether=2:3) to afford thetitle compound (130 mg, 87% yield) as a yellow solid. LCMS (ESI)[M+H]⁺=665.

Step 3:N-[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-methyl-phenyl]-2-chloro-benzenesulfonamidehydrochloride

To a mixture of tert-butylN-[4-[[4-[2-[4-[(2-chlorophenyl)sulfonylamino]-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate(100 mg, 0.15 mmol) in DCM (8 mL) was added HCl in dioxane (4 mL, 16mmol). The mixture was then stirred at room temperature for 0.5 h andthen concentrated. The residue was purified by prep-HPLC to give thetitle product (63 mg, 70% yield) as a white solid.

Example 2N-[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-fluoro-5-methyl-phenyl]-2-chloro-benzenesulfonamidehydrochloride Compound 102 Step 1:N-(3-Fluoro-4-hydroxy-phenyl)acetamide

To a solution of 4-amino-2-fluorophenol (3.29 g, 25.9 mmol) andtriethylamine (3.61 mL, 25.9 mmol) in methanol (130 mL) was added aceticanhydride (2.64 g, 25.9 mmol) at 0° C. The mixture was allowed to stirat 50° C. for 1.5 h. The solution was then concentrated in vacuo. Theresidue was purified by silica flash chromatography (petroleumether/ethyl acetate=1:2) to provide the title compound (1.0 g, 20%yield) as a brown solid. LCMS (ESI) [M+H]⁺=170.1.

Step 2: N-[3-(Diethylaminomethyl)-5-fluoro-4-hydroxy-phenyl]acetamide

To a mixture of N-(3-fluoro-4-hydroxy-phenyl)acetamide (210 mg, 1.24mmol) and paraformaldehyde (37 mg, 1.24 mmol) in ethanol (6 mL) wasadded diethylamine (0.26 mL, 2.48 mmol). The mixture was allowed to stirat 70° C. overnight then cooled to room temperature and subsequentlyconcentrated under vacuum. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=1:3) to provide the titlecompound (110 mg, 34% yield) as a gray solid. LCMS (ESI) [M+H]⁺=255.1.

Step 3: N-(3-Fluoro-4-hydroxy-5-methyl-phenyl)acetamide

To a solution ofN-[3-(diethylaminomethyl)-5-fluoro-4-hydroxy-phenyl]acetamide (230 mg,0.90 mmol) in methanol (5 mL) was added 10% Pd/C (50 mg). The mixturewas purged with H₂ 3 times and stirred at 50° C. for 3 days. The mixturewas filtered to give the title compound (160 mg, 96% yield) as a whitesolid. LCMS (ESI) [M+H]⁺=184.1.

Step 4: 4-Amino-2-fluoro-6-methyl-phenol hydrochloride

To a solution of N-(3-fluoro-4-hydroxy-5-methyl-phenyl)acetamide (160mg, 0.87 mmol) in 1,4-dioxane (4 mL) was added HCl (1 mL, 0.87 mmol).The mixture was stirred at 100° C. overnight and subsequentlyconcentrated in vacuo to afford the title compound (150 mg, 96% yield)as a yellow solid. LCMS (ESI) [M+H]⁺=142.1.

Step 5: tert-butyl((1r,4r)-4-((4-(2-(4-amino-2-fluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

A mixture of tert-butylN-[4-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]cyclohexyl]carbamate(150 mg, 0.39 mmol), 4-amino-2-fluoro-6-methyl-phenol hydrochloride (150mg, 0.84 mmol) and cesium carbonate (826 mg, 2.53 mmol) in DMSO (1 mL)was degassed for 3 times and stirred at 130° C. for 1.5 h under N₂. Themixture was concentrated in vacuo, and ethyl acetate (30 mL) was added.The mixture was washed with water, brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified byprep-TLC (petroleum ether/ethyl acetate=2:1) to give the title compound(140 mg, 71% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=509.3.

Step 6: tert-ButylN-[4-[[4-[2-[4-[(2-chlorophenyl)sulfonylamino]-2-fluoro-6-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate

To a solution of tert-butylN-[4-[[4-[2-(4-amino-2-fluoro-6-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate(140 mg, 0.28 mmol) in dry pyridine (2 mL) was added2-chlorobenzenesulfonylchloride (69 mg, 0.33 mmol) at 0° C. Aftercompletion of the addition, the reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated in vacuo The residuewas purified by prep-TLC (ethyl acetate:petroleum ether=1:1) to affordthe title compound (140 mg, 74% yield) as a yellow solid. LCMS (ESI)[M+H]⁺=683.2.

Step 7:N[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-fluoro-5-methyl-phenyl]-2-chloro-benzenesulfonamidehydrochloride

To a solution of tert-butylN-[4-[[4-[2-[4-[(2-chlorophenyl)sulfonylamino]-2-fluoro-6-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate(140 mg, 0.20 mmol) in DCM (4 mL) was added HCl in dioxane (2 mL, 2mmol). The mixture was then stirred at room temperature for 0.5 h andconcentrated in vacuo. The residue was purified by prep-HPLC to give thetitle compound (53 mg, 41% yield) as a white solid.

Example 3(S)—N-(2-Chlorophenylsulfonyl)-4-methyl-3-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)benzamidehydrochloride (Compound 103) Step 1: tert-Butyl(3S)-3-[[4-[2-(5-methoxycarbonyl-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

A mixture of tert-butyl(3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate(200 mg, 0.54 mmol), methyl 3-hydroxy-4-methyl-benzoate (106 mg, 0.64mmol) and cesium carbonate (348 mg, 1.07 mmol) in DMSO (3 mL) wasstirred at 130° C. for 2 h. The reaction mixture was diluted in ethylacetate (50 mL), washed with brine and then dried over anhydrous sodiumsulfate. Evaporation in vacuo gave the title product as a yellow solid(210 mg), which was used in the next step without further purification.LCMS (ESI): [M+H]⁺=520.3.

Step 2:3-[[3-[2-[[(3S)-1-tert-Butoxycarbonyl-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]-4-methyl-benzoicacid

A mixture of tert-butyl(3S)-3-[[4-[2-(5-methoxycarbonyl-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(210 mg, 0.40 mmol) and lithium hydroxide (14 mg, 0.61 mmol) in THF (10mL) was stirred at room temperature for 2 h. The mixture wasconcentrated and purified by prep-TLC (petroleum ether/ethylacetate=1/2) to give3-[[3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]-4-methyl-benzoic acid (160 mg, 78% yield)as a yellow solid. LCMS (ESI): [M+H]⁺=506.2.

Step 3: tert-Butyl(3S)-3-[[4-[2-[5-[(2-chlorophenyl)sulfonylcarbamoyl]-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

A mixture of3-[[3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]-4-methyl-benzoicacid (150 mg, 0.30 mmol), 2-chlorobenzenesulfonamide (74 mg, 0.39 mmol),l-ethyl-3-(3-dimethyllaminopropyl)carbodiimide (85 mg, 0.45 mmol),N-hydroxybenzotrizole (60 mg, 0.45 mmol) and N,N-diisopropylethylamine(76 mg, 0.59 mmol) in DCM (15 mL) was stirred at room temperature for 16h. The mixture was concentrated in vacuo to give the crude product (150mg) as a yellow oil, which was used in the next step without furtherpurification. LCMS (ESI): [M+H]⁺=679.2.

Step 4:N-(2-Chlorophenyl)sulfonyl-4-methyl-3-[[3-[2-[[(3S)-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]benzamidehydrochloride

To a solution of tert-butyl(3S)-3-[[4-[2-[5-[(2-chlorophenyl)sulfonylcarbamoyl]-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(150 mg, 0.22 mmol) in DCM (10 mL) was added hydrochloric acid (4 M in1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperaturefor 1 h, concentrated in vacuo and purified by prep-HPLC to give thetitle compound (27.5 mg, 20% yield) as a white solid.

Example 4N-[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-chloro-5-fluoro-phenyl]-2-chloro-benzenesulfonamidehydrochloride (Compound 104) Step 1:2-Chloro-N-(3-chloro-5-fluoro-4-methoxy-phenyl)benzenesulfonamide

To a solution of 3-chloro-5-fluoro-4-methoxy-aniline (1.0 g, 5.7 mmol)in pyridine (10 mL) was added 2-chlorobenzenesulfonylchloride (1.44 g,6.83 mmol) at 0° C. After completion of the addition, the reactionmixture was stirred at 20° C. overnight. The reaction mixture was thenconcentrated in vacuo. The crude product was purified by silica flashchromatography (petroleum ether/ethyl acetate=6/1) to give the titlecompound (1.9 g, 95% yield) as a yellow solid. LCMS (ESI): [M+H₂O]⁺=367.

Step 2:2-Chloro-N-(3-chloro-5-fluoro-4-hydroxy-phenyl)benzenesulfonamide

A mixture of2-chloro-N-(3-chloro-5-fluoro-4-methoxy-phenyl)benzenesulfonamide (230mg, 0.66 mmol) and tribromoborane (2.05 mL, 2.05 mmol) in DCM (5 mL) wasstirred at 0° C. for 16 h. Then, methanol was added and the solvent andtrimethyl borate were removed in vacuo. The residue was dissolved inmethanol and the solution was evaporated again under reduced pressure toremove traces of trimethyl borate. The solid residue was dissolved inethyl acetate, and the solution was washed with water and dried withanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the crude product was purified by prep-TLC (ethylacetate/petroleum ether=1/4) to provide the title compound (220 mg, 99%yield) as a yellow oil. LCMS (ESI): [M+Na]⁺=358.

Step 3: tert-ButylN-[4-[[4-[2-[2-chloro-4-[(2-chlorophenyl)sulfonylamino]-6-fluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate

A mixture of2-chloro-N-(3-chloro-5-fluoro-4-hydroxy-phenyl)benzenesulfonamide (220mg, 0.65 mmol), tert-butylN-[4-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]cyclohexyl]carbamate(253 mg, 0.65 mmol) and cesium carbonate (213 mg, 0.65 mmol) in DMSO (5mL) was stirred at 110° C. for 2 h, then concentrated and purified byprep-TLC (petroleum ether/ethyl acetate=1/2) to give the title compound(130 mg, 28% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=703.

Step 4:N-[4-[[3-[2-[(4-Aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridyl]oxy]-3-chloro-5-fluoro-phenyl]-2-chloro-benzenesulfonamidehydrochloride

A mixture of tert-butylN-[4-[[4-[2-[2-chloro-4-[(2-chlorophenyl)sulfonylamino]-6-fluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]carbamate(130 mg, 0.18 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 1.5 mL,1.5 mmol) in DCM (1.5 mL) was stirred at room temperature for 1 h. Themixture was concentrated and the residue purified by prep-HPLC to givethe title compound (87 mg, 73% yield) as a white solid.

Example 5(S)-3,3,3-Trifluoro-N-(2-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride (Compound 105) Step 1:2-Chloro-4-(2-fluoropyridin-3-yl)pyrimidine

To a mixture of 2,4-dichloropyrimidine (10.0 g, 67.1 mmol) and(2-fluoropyridin-3-yl)boronic acid (11.4 g, 80.6 mmol) in dioxane (130mL) and H₂O (50.0 mL) was added tetrakis(triphenylphosphine)palladium(0)(3.88 g, 3.36 mmol) and potassium carbonate (20.0 g, 144 mmol) in oneportion at 25° C. under N₂. The mixture was then stirred at 90° C. for18 h at which LCMS showed that the reaction was complete. The mixturewas cooled to 25° C. and poured into water (100 mL). The aqueous phasewas extracted with ethyl acetate, and the organic extract was washedtwice with brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (petroleum ether/EtOAc=1/0, 5/1) to afford the titlecompound (6.00 g, 42.6% yield) as an off-white solid.

Step 2: tert-Butyl(S)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine (75 g, 358 mmol),tert-butyl (3S)-3-aminopiperidine-1-carboxylate (57.3 g, 286.2 mmol),N,N-diisopropylethylamine (187.5 mL 1.07 mol), and cesium fluoride (13.2mL, 357.81 mmol,) in DMSO (1.40 L) was degassed and purged with N₂ 3times. The mixture was then stirred at 80° C. for 3 h under N₂atmosphere. LCMS showed that most of the starting material was consumed,and the desired mass was detected. The reaction mixture was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicacolumn chromatography (petroleum ether/ethyl acetate=2/1) andrecrystallized by petroleum ether/ethyl acetate=1/1 to afford the titlecompound (54 g, 39.6% yield) as a white solid. LCMS (ESI): [M+H]⁺=374;¹H NMR (400 MHz, CDCl₃) δ 8.77-8.45 (m, 1H), 8.36 (d, 0.7=4.9 Hz, 1H),8.26 (d, J=3.1 Hz, 1H), 7.31 (t, J=5.4 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H),5.49 (br s, 1H), 4.08-3.91 (m, 1H), 3.91-2.99 (m, 3H), 1.98 (br s, 1H),1.74 (d, J=6.4 Hz, 1H), 1.59 (d, J=6.7 Hz, 2H), 1.37 (s, 9H)

Step 3: tert-Butyl(S)-3-((4-(2-(4-amino-3-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a mixture of tert-butyl(S)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(1.21 g, 3.23 mmol) and 4-amino-3-fluorophenol (534 mg, 4.2 mmol) inDMSO (8 mL) was added cesium carbonate (1.52 g, 4.65 mmol) in oneportion. The mixture was stirred at 130° C. for 1.5 h. Water was addedand the mixture was extracted 3 times with ethyl acetate. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (petroleumether/ethyl acetate=1/1) to afford the title compound (420 mg, 27.2%yield) as a brown solid.

Step 4: tert-Butyl(S)-3-((4-(2-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-[[4-[2-(4-amino-3-fluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(150 mg, 0.312 mmol) in chloroform (2.00 mL) and N-methylmorpholine (103μL, 0.937 mmol) was added 3,3,3-trifluoropropane-1-sulfonyl chloride(61.36 mg, 312.16 umol, 1.00 equiv.) at 0° C., and the mixture wasstirred at 25° C. for 1 h. The residue was purified by prep-TLC(petroleum ether/ethyl acetate=1:1.5) to afford the title compound (81.5mg, 41% yield) as a white solid.

Step 5:(S)-3,3,3-Trifluoro-N-(2-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride

A mixture of tert-butyl(S)-3-((4-(2-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenoxy)pyridin-3-yl) pyrimidin-2-yl)amino)piperidine-1-carboxylate (171mg, 0.267 mmol) in hydrochloric acid (4 M in ethyl acetate, 15 mL) wasstirred at 15° C. for 1 h. The mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC to afford the title compound (65.4 mg,45% yield) as a yellow solid.

Example 6N-(2,3-Difluoro-4-((3-(2-(((3S,5R)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride (Compound 111) Step 1: Benzyl(3S,5R)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate

To a mixture of 2-chloro-4-(2-fluoropyridin-3-yl)pyrimidine (6.04 g,24.3 mmol) in DMSO (110 mL) was added benzyl(3S,5R)-3-amino-5-methylpiperidine-1-carboxylate (6 g, 28.6 mmol),N,N-diisopropylethylamine (15 mL, 85.9 mmol,) and cesium carbonate (4.35g, 28.6 mmol) at 20° C. The reaction mixture was degassed and purgedwith N₂ 3 times. The mixture was then stirred at 80° C. for 3 h under N₂atmosphere. The mixture was cooled to ° C., quenched with water (100 mL)and extracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica column chromatography (petroleum ether/ethylacetate=15/1 to 6/1) to give the title compound (6.5 g, 51% yield) as alight yellow solid. LCMS (ESI): [M+H]⁺=422.

Step 2: Benzyl(3S,5R)-3-((4-(2-(4-amino-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate

A mixture of benzyl(3S,5R)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate(1 g, 2.37 mmol), 4-amino-2,3-difluorophenol (344 mg, 2.37 mmol), cesiumcarbonate (928 mg, 2.85 mmol) in DMSO (20 mL) was degassed and purgedwith N₂ 3 times. The mixture was stirred at 130° C. for 1.5 h under N₂atmosphere and then cooled to room temperature. Water was added, and themixture was then extracted with ethyl acetate. The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica column chromatography(petroleum ether/ethyl acetate=20/1 to 1:1) to provide the titlecompound (3.9 g, 43% yield) as a brown solid.

Step 3: Benzyl(3S,5R)-3-((4-(2-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate

To a solution of benzyl(3S,5R)-3-((4-(2-(4-amino-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate(3.4 g, 6.22 mmol) in CHCl₃ (68 mL) and N-methylmorpholine (1.89 g, 18.7mmol) was added phenylmethanesulfonyl chloride (1.19 g, 6.22 mmol) at 0°C. The mixture was stirred at 25° C. for 14 h. The reaction mixture wasquenched with sat aqueous NaHCO₃ and extracted with DCM. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography (petroleum ether/ethyl acetate=20:1 to 2:1) to givecompound the title compound (2 g, 34.6% yield) as a brown solid.

Step 4:N-(2,3-Difluoro-4-((3-(2-(((3S,5R)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

To a solution of benzyl(3S,5R)-3-((4-(2-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate(2 g, 2.15 mmol) in DCM (20 mL) and CH₃CN (20 mL) was addeddimethylsulflde (8.02 g, 129 mmol) and boron trifluoride diethyletherate (9.16 g, 64.5 mmol). The reaction mixture was stirred at 25° C.for 3 h. The mixture was then diluted with ethyl acetate, washed withsaturated NaHCO₃(aq), and then extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC and lyophilized to provide the title compound(650 mg, 50.1% yield) as a white solid.

Example 7(S)-2-Chloro-N-(3-fluoro-5-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 114) Step 1: (S)-tert-Butyl3-((4-(2-(4-amino-2-fluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a stirred solution of (S)-tert-butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(2.02 g, 5.41 mmol) in DMSO (18 mL) was added cesium carbonate (6.60 g,20.27 mmol) and 4-amino-2-fluoro-6-methylphenol hydrochloride (1.2 g,6.76 mmol). The mixture was stirred at 130° C. for 13 h. After coolingto room temperature, the mixture was diluted with ethyl acetate (20 mL),washed with water (20 mL) and brine (20 mL×2). The organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica flash chromatography (ethylacetate/petroleum ether=2:1) to give the title compound (2.2 g, 59%yield) as a yellow solid. LCMS (ESI) [M+Na]^(+=517.1.)

Step 2: (S)-tert-Butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)-2-fluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of (S)-tert-butyl3-((4-(2-(4-amino-2-fluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(110 mg, 0.22 mmol) in pyridine (2 mL) was added2-chlorobenzene-1-sulfonyl chloride (70 mg, 0.33 mmol). The mixture wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated in vacuo and the residue was diluted with ethyl acetate (30mL), washed with water (30×2 mL) and brine (30 mL). The organic phasewas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the title compound (120 mg crude) as a brown solid, which was usedin the next step without further purification. LCMS (ESI) [M+H]⁺=669.1.

Step 3:(S)-2-Chloro-N-(3-fluoro-5-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)-2-fluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(110 mg, 0.16 mmol) in DCM (2 mL) was added 4 M HCl in ethyl acetate(0.12 mL, 0.49 mmol). The mixture was stirred at room temperature for 1h. The mixture was concentrated in vacuo, and the residue was purifiedby prep-HPLC (acetonitrile 17-47%/0.05% HCl in water) to give the titlecompound (36 mg, 35% yield) as a white solid.

Example 8N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3,5-difluorophenyl)propane-1-sulfonamidehydrochloride (Compound 122) Step 1: tert-Butyl((1r,4r)-4-((4-(2-(4-amino-2,6-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1r,4r)-4-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(100 mg, 0.26 mmol) in DMSO (3 mL) was added 4-amino-2,6-difluorophenol(45 mg, 0.31 mmol) and cesium carbonate (252 mg, 0.77 mmol). The mixturewas stirred at 120° C. for 2 h. After cooling to room temperature, themixture was diluted with ethyl acetate (20 mL), washed with water (20mL) and brine (20 mL×2). The organic phase was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica flash chromatography (petroleum ether/ethylacetate=1/1) to give the title compound (80 mg, 61% yield) as a yellowsolid. LCMS (ESI) [M+Na]⁺=535.4.

Step 2: tert-Butyl((1r,4r)-4-((4-(2-(2,6-difluoro-4-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a solution of tert-butyl((1r,4r)-4-((4-(2-(4-amino-2,6-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(80 mg, 0.16 mmol) in pyridine (2 mL) was added propane-1-sulfonylchloride (27 mg, 0.19 mmol). The mixture was stirred at room temperaturefor 12 h and concentrated in vacuo. The residue was diluted with ethylacetate (20 mL), washed with water (20×2 mL) and brine (20 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (100 mg crude) as a brown solid,which was used in the next step without further purification. LCMS (ESI)[M+H]⁺=619.4.

Step 3:N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3,5-difluorophenyl)propane-1-sulfonamidehydrochloride

To a solution of tert-butyl((1r,4r)-4-((4-(2-(2,6-difluoro-4-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(100 mg, 0.16 mmol) in DCM (3 mL) was added 4M hydrochloric acid (0.12mL, 0.48 mmol) in ethyl acetate. The mixture was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo and theresidue purified by prep-HPLC (acetonitrile 15-45%/0.05% HCl in water)to give the title compound (22 mg, 24% yield) as a yellow solid.

Example 9N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-chloro-5-fluorophenyl)propane-1-sulfonamidehydrochloride (Compound 121) Step 1: 4-Amino-2-chloro-6-fluorophenol

To a solution of 3-chloro-5-fluoro-4-methoxy-aniline (200 mg, 1.14 mmol)in DCM (8 mL) was added tribromoborane (0.33 mL, 3.42 mmol) at −78° C.The reaction was warmed up to room temperature and then stirred at roomtemperature for 16 h. The reach (Mi was quenched with saturated aqueousNaHCO₃ and extracted with ethyl acetate (20 mL). The organic phase waswashed with water (20×2 mL), brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicaflash chromatography (petroleum ether/ethyl acetate=3/1) to give thetitle compound (120 mg, 65% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.88 (s, 1H), 6.42-6.37 (m, 1H), 6.37-6.31 (m, 1H), 5.05 (s,2H).

Step 2: tert-Butyl((1r,4r)-4-((4-(2-(4-amino-2-chloro-6-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1r,4r)-4-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(200 mg, 0.52 mmol) in DMSO (3 mL) was added cesium carbonate (505 mg,1.55 mmol) and 4-amino-2-chloro-6-fluorophenol (125 mg, 0.77 mmol). Themixture was stirred at 120° C. for 2 h. After cooling to roomtemperature, the mixture was diluted with ethyl acetate (20 mL), washedwith water (20×2 mL), and brine (20 mL). The organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by silica flash chromatography (petroleumether/ethyl acetate=1/1) to give the title compound (80 mg, 29% yield)as a brown solid. LCMS (ESI) [M+H]⁺=529.1.

Step 3: tert-Butyl((1r,4r)-4-((4-(2-(2-chloro-6-fluoro-4-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a solution of tert-butyl((1r,4r)-4-((4-(2-(4-amino-2-chloro-6-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(80 mg, 0.15 mmol) in pyridine (2 mL) was added propane-1-sulfonylchloride (26 mg, 0.18 mmol). The mixture was stirred at room temperaturefor 12 h and concentrated in vacuo. The residue was diluted with ethylacetate (30 mL), washed with water (30×2 mL) and brine (30 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (100 mg crude) as a brown solid,which was used in the next step without further purification. LCMS (ESI)[M+Na]⁺=657.2.

Step 4:N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-chloro-5-fluorophenyl)propane-1-sulfonamidehydrochloride

A solution of tert-butyl((1r,4r)-4-((4-(2-(2-chloro-6-fluoro-4-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(100 mg, 0.16 mmol) in DCM (2 mL) was added 4M hydrochloric acid (0.12mL, 0.48 mmol) stirred at room temperature for 2 h. The mixture wasconcentrated in vacuo and the residue purified by prep-HPLC to give thetitle compound (20 mg, 21% yield) as a yellow solid.

Example 10(S)-2-Chloro-N-(2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamide(Compound 123) Step 1: tert-Butyl(S)-3-((4-(2-(4-amino-2,3-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl(3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate200 mg, 0.53 mmol), 4-amino-2,3-dimethyl-phenol (110.2 mg, 0.80 mmol),and cesium carbonate (349.0 mg, 1.07 mmol) in DMSO (2 mL) was heated at120° C. for 3 h. The mixture was then cooled and diluted with water. Theprecipitate was filtered and the aqueous layer extracted with iPrOAc(2×20 mL). The combined organics were washed with brine, dried overMgSO₄, filtered, concentrated in vacuo, and dried under high vacuum toafford 246 mg (93.6% yield) of the title compound as a brown solid. Thecrude material was carried on without further purification. LCMS (ESI)[M+H]⁺=491.3

Step 2: tert-Butyl(S)-3-((4-(2-(4-((2-chlorophenyl)sulfonamido)-2,3-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of tert-butyl(3S)-3-[[4-[2-(4-amino-2,3-dimethyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(123 mg, 0.25 mmol) and 2-chlorobenzenesulfonyl chloride (79.4 mg, 0.38mmol) in pyridine (1 mL) was stirred at room temperature overnight. Itwas diluted with water, extracted with iPrOAc (2×10 mL), dried overMgSO₄, filtered, concentrated in vacuo, and dried under high vacuum toafford 157 mg (94.1% yield) of the title compound as a brown solid. Thecrude material was carried on without further purification. LCMS (ESI)[M+H]⁺=665.2.

Step 3:(S)-2-Chloro-N-(2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamide

tert-Butyl(3S)-3-[[4-[2-[4-[(2-chlorophenyl)sulfonylamino]-2,3-dimethyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(157 mg, 0.24 mmol) was treated with a mixture of 4N HCl/dioxane (2 mL)and 1.25N HCl/EtOH (1 mL) at room temperature for 1 h. It wasconcentrated in vacuo and dried under high vacuum. The crude materialwas purified by prep-HPLC to afford 78.6 mg (59% yield) of the titlecompound as a brown solid.

Example 11(S)-2-Cyclohexyl-N-(2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)acetamide(Compound 129) Step 1: tert-Butyl(S)-3-((4-(2-(4-(2-cyclohexylacetamido)-2,3-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl(3S)-3-[[4-[2-(4-amino-2,3-dimethyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(115 mg, 0.23 mmol), 2-cyclohexylacetic acid (50.0 mg, 0.35 mmol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (181.9 mg, 0.47 mmol) in DMF (1.5 mL) wasadded N,N-diisopropylethylamine (0.12 mL, 0.70 mmol). The reactionmixture was stirred at room temperature overnight. It was diluted withwater, extracted with isoprpylacetate (2×10 mL), dried over anhydrousMgSO₄, filtered, and concentrated in vacuo. Purification by silica gelchromatography (12 g column; elution with 0-5% MeOH/DCM) afforded 96 mg(66% yield) of the title compound as a yellow solid. LCMS (ESI)[M+H]⁺=615.1.

Step 2:(S)-2-Cyclohexyl-N-(2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)acetamide

tert-Butyl(3S)-3-[[4-[2-[4-[(2-cyclohexylacetyl)amino]-2,3-dimethyl-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(96 mg, 0.15 mmol) was treated with a mixture of 4N HCl/dioxane (2 mL)and 1.25N HCl/EtOH (1 mL) at room temperature for 1 h. The mixture wasconcentrated in vacuo and dried under high vacuum. The crude materialwas purified by reverse phase prep-HPLC to afford 53.8 mg (67% yield) ofthe title compound as an off-white solid.

Example 12(S)-2-Chloro-N-(3,5-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 131) Step 1: (S)-tert-Butyl3-((4-(2-(2,6-dimethyl-4-nitrophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A flask was charged with (S)-tert-butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(100 mg, 0.27 mmol), 2,6-dimethyl-4-nitrophenol (45 mg, 0.15 mmol), andcesium carbonate (176 mg, 0.54 mmol) in that order. To the mixture wasthen added N-methyl-pyrrolidinone (0.3 mL) and the mixture placed in a160° C. oil bath overnight. After 16 h, the mixture was purifieddirectly by C18 reverse phase flash chromatography (50-100% ACN/10 mMaqueous ammonium formate, pH=3.8). The product-containing fractions werecombined and most of the ACN removed under reduced pressure, followed bydilution with EtOAc and separation of the phases. The organic extractwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toprovide the title compound (40 mg, 28% yield) as a yellow solid. LCMS(ESI) [M+H]⁺=521.3. ¹H NMR (500 MHz, CDCl₃) δ 8.93-8.39 (br s, 1H), 8.19(s, 1H), 8.07 (d, J=3.2 Hz, 1H), 7.97 (s, 2H), 7.45 (s, 1H), 7.13 (dd,J=7.2, 5.1 Hz, 1H), 4.36-3.71 (m, 2H), 3.60 (s, 1H), 3.45-2.75 (m, 3H),2.10 (s, 6H), 2.03-1.92 (m, 1H), 1.84-1.70 (m, 1H), 1.65 (ddd, J=13.0,9.0, 4.5 Hz, 1H), 1.61-1.50 (m, 1H), 1.50-1.22 (m, 9H).

Step 2: (S)-tert-Butyl3-((4-(2-(4-amino-2,6-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of (S)-tert-butyl3-((4-(2-(2,6-dimethyl-4-nitrophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(35 mg, 0.067 mmol) and nickel(II)chloride hexahydrate (8.0 mg, 0.03mmol) in a mixture of MeOH (0.3 mL) and THF (0.3 mL) was cooled to 0° C.and NaBH₄ (13 mg, 0.34 mmol) was added. After 5 min, the mixture wasdiluted with 1M HCl (3 mL) and stirred 5 min at room temperature to givea homogeneous solution. The solution was then treated with concentratedaqueous NH₄OH (10 mL) and diluted with EtOAc. The phases were separatedand the aqueous phase extracted again with EtOAc. The organic extractswere combined, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude material was dissolved in MeOH (5 mL) and heated at100° C. in a microwave reactor for 10 min. Subsequent concentration invacuo provided the title compound (31 mg, 94% yield) as a beige solid.LCMS (ESI) [M+H]⁺=491.2. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (brs, 1H), 8.27(d, J=4.8 Hz, 1H), 8.09 (dd, J=4.8, 1.9 Hz, 1H), 7.53 (d, J=3.8 Hz, 1H),7.00 (dd, J=7.5, 4.8 Hz, 1H), 6.39 (s, 2H), 5.39 (br s, 3H), 4.06-3.95(m, 1H), 3.56-3.45 (m, 1H), 3.36-2.97 (m, 3H), 1.97-1.91-1.91 (m, 7H),1.74-1.66 (m, 1H), 1.66-1.52 (m, 2H), 1.40-1.25 (m, 9H).

Step 3: (S)-tert-Butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)-2,6-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of (S)-tert-butyl3-((4-(2-(4-amino-2,6-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(31 mg, 0.063 mmol) in pyridine (0.3 mL) was added2-chlorobenzenesulfonylchloride (18 mg, 0.08 mmol) and the mixturestirred at room temperature. After 16 h, the mixture was directlypurified by C18 reverse phase flash chromatography (40-90% ACN/10 mMaqueous ammonium formate, pH=3.8). The product-containing fractions werecombined and lyophilized to provide the title compound (25 mg, 60%yield). LCMS (ESI) [M+H]⁺=665.2. ¹H NMR (500 MHz, CDCl₃) δ 8.80-8.30 (brs, 1H), 8.19 (s, 1H), 8.02 (dd, J=4.7, 1.7 Hz, 1H), 7.98 (dd, J=7.9, 1.3Hz, 1H), 7.53-7.36 (m, 3H), 7.31 (dd, J=11.0, 4.2 Hz, 1H), 7.02 (dd,J=7.5, 4.9 Hz, 1H), 6.94 (s, 1H), 6.81 (s, 2H), 4.01-3.91 (m, 1H),3.64-3.04 (m, 5H), 1.94 (s, 7H), 1.78-1.68 (m, 1H), 1.62-1.52 (m, 2H),1.40-1.23 (m, 9H).

Step 4:(S)-2-Chloro-N-(3,5-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)-2,6-dimethylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(25 mg, 0.038 mmol) in 1,4-dioxane (0.19 mL) at 0° C. was added 4N HClin dioxane (0.1 mL, 0.4 mmol) and the mixture stirred at roomtemperature. After 3 h, the mixture was concentrated in vacuo and thecrude residue was purified by C18 reverse phase flash chromatography(20-60% ACN/10 mM aqueous ammonium formate, pH=3.8). The productcontaining fractions were combined and lyophilized to provide the freebase material. This free base material was diluted with 1,4-dioxane(0.19 mL) and then treated with 4N HCl in dioxane (0.05 mL, 0.2 mmol)followed by concentration in vacuo to provide the HCl salt. The salt wasdissolved in a mixture of ACN and H₂O and lyophilized to provide thetitle product (23 mg, 75% yield) as a white solid.

Example 13(S)-2-Chloro-N-(3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 132) Step 1: (S)-tert-Butyl3-((4-(2-(3-aminophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

-   -   To a solution of 3-aminophenol (141 mg, 1.30 mmol) in DMSO (4.8        mL) was added (S)-tert-butyl        3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate        (440 mg, 1.18 mmol) followed by cesium carbonate (811 mg, 2.47        mmol), and the mixture was placed in a 120° C. oil bath        overnight. After 16 h, the mixture was diluted with H₂O and        EtOAc, and the phases were separated. The organic extract was        washed with 1N NaOH, then with saturated aqueous NaCl, dried        over anhydrous MgSO₄, filtered and concentrated in vacuo to        provide the crude title compound (680 mg), which was used in the        next step without further purification. LCMS (ESI) [M+H]⁺=463.0.

Step 2: (S)-tert-Butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-aminophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(80 mg, 0.17 mmol) in DCM (0.58 mL) was added2-chlorobenzenesulfonylchloride (73 mg, 0.35 mmol), followed by additionof pyridine (0.21 mL, 2.59 mmol). The mixture was stirred at roomtemperature, and after 2 h, volatiles were removed in vacuo. The cruderesidue was purified by C18 reverse phase flash chromatography (40-80%ACN/10 mM aqueous ammonium formate, pH=3.8). The product-containingfractions were combined and diluted with EtOAc and saturated aqueousNaHCO₃, and the phases were separated. The organic extract was washedwith saturated aqueous NaCl, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to provide the tide compound (43 mg, 39% yield).LCMS (ESI) [M+H]⁺=637.2.

Step 3:(S)-2-Chloro-N-(3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(43 mg, 0.07 mmol) in 1,4-dioxane (0.31 mL) was added 4N HCl in dioxane(1.0 mL, 4.0 mmol) and the mixture was stirred at room temperature.After 90 min, the mixture was diluted with diethyl ether and theresulting solids filtered off, washed with diethyl ether, dissolved in amixture of ACN and H₂O and lyophilized to provide the title product (40mg, 100% yield) as a white solid.

Example 14(S)-1-Phenyl-N-(3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 133) Step 1: (S)-tert-Butyl3-((4-(2-(3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-aminophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(80 mg, 0.17 mmol) in DCM (0.58 mL) was addedphenylmethanesulfonylchloride (66 mg, 0.35 mmol) followed by addition ofpyridine (0.21 mL, 2.59 mmol). The mixture was stirred at roomtemperature and after 2.5 h, volatiles were removed in vacuo. The cruderesidue was purified by C18 reverse phase flash chromatography (40-80%ACN/10 mM aqueous ammonium formate, pH=3.8). The product-containingfractions were combined and diluted with EtOAc and saturated aqueousNaHCO₃, and the phases were separated. The organic extract was washedwith saturated aqueous NaCl, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to provide the tide compound (49 mg, 46% yield).LCMS (ESI) [M+H]⁺=617.1.

Step 2:(S)-1-Phenyl-N-(3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(45 mg, 0.07 mmol) in 1,4-dioxane (0.36 mL) was added 4N HCl in dioxane(1.0 mL, 4.0 mmol) and the mixture was stirred at room temperature.After 90 min, the mixture was diluted with Diethyl ether and theresulting solids were filtered off, washed with Diethyl ether, dissolvedin a mixture of ACN and H₂O and lyophilized to provide the title product(42 mg, 100% yield) as a white solid.

Example 15(S)-2-Chloro-N-(4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 134) Step 1: (S)-tert-Butyl3-((4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of (S)-tert-butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(200 mg, 0.54 mmol), 4-aminophenol (64 mg, 0.59 mmol), and cesiumcarbonate (369 mg, 1.12 mmol) in DMSO (2 mL) was placed in a 120° C. oilbath sealed. After 2 h, the mixture was diluted with EtOAc (75 mL),washed with H₂O (10 mL) and then with 50% saturated aqueous NaCl (4×10mL). Drying (Na₂SO₄), filtration through a short pad of silica geltopped with celite and concentration in vacuo provided the titlecompound (186 mg, 75% yield) as a brown wax which was used in the nextstep without further purification. LCMS (ESI) [M+H]⁺=463.2.

Step 2: (S)-tert-Butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(60 mg, 0.13 mmol) in a mixture of DCM (2 mL) and pyridine (1 mL) wasadded 2-chlorobenzenesulfonylchloride (68 mg, 0.32 mmol) and the mixturestirred at room temperature. After 4 h, the mixture was diluted with DCM(50 mL), washed with saturated aqueous NaHCO₃ solution (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was then purified by silica flash chromatography (0-100%EtOAc/hexanes) to provide the title compound (67 mg, 81% yield) as ayellow wax. LCMS (ESI) [M+H]⁺=637.0.

Step 3:(S)-2-Chloro-N-(4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(4-(2-chlorophenylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(67 mg, 0.11 mmol) in EtOAc (2 mL) was added 4N HCl in dioxane (2.0 mL,8.0 mmol) and the mixture stirred at room temperature. After 3 h,volatiles were removed under reduced pressure and the crude HCl saltresidue was washed with EtOAc (3×3 mL), then ACN (3×3 mL). The cruderesidue was then sonicated with ACN (3 mL) to produce a suspension andvolatiles were removed under reduced pressure (process was repeated 3times). The resulting solids were dissolved in a mixture of H₂O and ACNand lyophilized to provide the title product (35 mg, 58% yield) as awhite solid. LCMS (ESI) [M+H]⁺=537.0.

Example 16(S)-2-Chloro-N-(4-methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 135) Step 1: (S)-tert-Butyl3-((4-(2-(5-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of (S)-tert-butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(200 mg, 0.54 mmol), 5-amino-2-methylphenol (72 mg, 0.59 mmol), andcesium carbonate (369 mg, 1.12 mmol) in DMSO (1.8 mL) was placed in anoil bath that was heated to 120° C. After 3 h, the mixture was dilutedwith EtOAc (75 mL), washed with H₂O (10 mL), then with saturated aqueousNaCl solution (10 mL), dried over MgSO₄, filtered and concentrated invacuo to provide the title compound (278 mg, quant. yield) as a brownfoam which was used in the next step without further purification. LCMS(ESI) [M+H]⁺=477.3.

Step 2: (S)-tert-Butyl3-((4-(2-(5-(2-chlorophenylsulfonamido)-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(5-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(63 mg, 0.13 mmol) in DCM (0.5 mL) was added2-chlorobenzenesulfonylchloride (33 mg, 0.16 mmol) and pyridine (0.16mL), and the mixture was stirred at room temperature. After 16 h, afurther portion of 2-chlorobenzenesulfonylchloride (15 mg, 0.07 mmol)was added. After 2 h at room temperature, the volatiles were removedunder reduced pressure and the crude residue purified by C18 reversephase flash chromatography (40-80% ACN/10 mM aqueous ammonium formate,pH=3.8). The product-containing fractions were combined and most of theACN was removed on a rotovap. The residue was then diluted with EtOAcand saturated aqueous NaHCO₃, and the phases were separated. The organicextract was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to provide the title compound (90 mg, 100% yield). LCMS (ESI)[M+H]⁺=651.1.

Step 3:(S)-2-Chloro-N-(4-methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(5-(2-chlorophenylsulfonamido)-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(86 mg, 0.13 mmol) in 1,4-dioxane (0.5 mL) was added 4N HCl in dioxane(1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature.After 90 min, the mixture was diluted with diethyl ether and theresulting solids were filtered off, washed with diethyl ether, dissolvedin a mixture of ACN and H₂O and lyophilized to provide the title product(73 mg, 94% yield) as a white solid.

Example 17(S)—N-(4-Methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride (Compound 136) Step 1: (S)-tert-Butyl3-((4-(2-(2-methyl-5-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(5-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(63 mg, 0.13 mmol) in DCM (0.58 mL) was added phenylmethanesulfonylchloride (38 mg, 0.20 mmol) and pyridine (0.16 mL) and the mixturestirred at room temperature overnight. After 16 h, the volatiles wereremoved in vacuo and the crude residue purified by C18 reverse phaseflash chromatography (40-80% ACN/10 mM aqueous ammonium formate,pH=3.8). The product-containing fractions were combined and most of theACN was removed under reduced pressure. The residue was diluted withEtOAc and saturated aqueous NaHCO₃, and the phases were separated. Theorganic extract was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to provide the title compound (63 mg, 76% yield).LCMS (ESI) [M+H]⁺=631.1.

Step 2:(S)—N-(4-Methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(2-methyl-5-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(63 mg, 0.10 mmol) in 1,4-dioxane (0.4 mL) was added 4N HCl in dioxane(1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature.After 90 min, the mixture was diluted with Diethyl ether, and theresulting solids were filtered off, washed with Diethyl ether, dissolvedin a mixture of ACN and H₂O and lyophilized to provide the title product(41 mg, 72% yield) as a white solid.

Example 18(S)—N-(2,3-Difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1-(pyridin-2-yl)methanesulfonamide(Compound 238) Step 1: tert-Butyl(3S)-3-[[4-[2-[2,3-difluoro-4-(2-pyridylmethylsulfonylamino)phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

To a vial containing tert-butyl(3S)-3-[[4-[2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(200 mg, 0.40 mmol) was added DCM (4 mL) followed by triethylamine (0.22mL, 1.61 mmol) and (2-pyridylmethyl)sulfonylchloride triflate (288.6 mg,0.80 mmol). The reaction mixture was stirred at room temperature for 16h, quenched with 10 mL of saturated aqueous bicarbonate solution, andDCM was added. The organic extract was dried with magnesium sulfate,filtered and concentrated to afford the title compound as a crudeintermediate (quantitative yield). This product was used in the nextstep without further purification. LCMS (ESI): [M+1]⁺=654.

Step 2:(S)—N-(2,3-Difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1-(pyridin-2-yl)methanesulfonamide

To a vial containing tert-butyl(3S)-3-[[4-[2-[2,3-difluoro-4-(2-pyridylmethylsulfonylamino)phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylatein DCM (5 mL) was added 4M HCl in 1,4 dioxane (1.5 mL), and the reactionmixture was stirred at room temperature for 2 h. Concentration todryness under vacuum and purification by prep-HPLC afforded 112.7 mg(51% yield) of the title compound.

Example 19(S)-2-Chloro-N-(4-chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 137) Step 1:(3-Amino-6-chloro-2-fluorophenyl)boronic acid

A solution of 4-chloro-2-fluoroaniline (750 mg, 5.15 mmol) in THF (6.9mL) was cooled to −78° C. and n-BuLi (2.5 M in hexanes, 2.21 mL, 5.51mmol) was added. After stirring at −78° C. for 30 min,1,2-bis(chlorodimethylsilylethane) (1.16 g, 5.41 mmol) was added andafter 1 h at −78° C. a further portion of n-BuLi (2.5 M in hexanes, 2.27mL, 5.67 mmol) was added and the cooling bath was removed. After 1 h atroom temperature, the mixture was cooled back down to −78° C. and afurther portion of n-BuLi (2.5 M in hexanes, 2.37 mL, 5.93 mmol) wasadded. After 90 min at −78° C., triisopropyl borate (2.90 g, 3.57 mL,15.5 mmol) was added and the cooling bath was removed followed bystirring at room temperature overnight. After 16 h, the mixture wasdiluted with 1M HCl and stirred 1 h at room temperature. The organicphase was extracted with EtOAc, and the organic extracts were washedwith 1N sodium hydroxide, and the aqueous phase was re-extracted withEtOAc. The combined organic extracts were washed with saturated aqueousNaCl solution, dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue was triturated with a mixture of DCM, and hexanes andthe resulting solids were filtered to provide the title compound (425mg, 44% yield) as a white solid. ¹H NMR (400 MHz, d₆-DMSO) δ 8.51 (s,2H), 6.85 (dd, J=8.4, 0.6 Hz, 1H), 6.66 (dd, J=10.0, 8.5 Hz, 1H), 5.13(s, 2H).

Step 2: (S)-tert-Butyl3-((4-(2-(3-amino-6-chloro-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a suspension of (3-amino-6-chloro-2-fluorophenyl)boronic acid (150mg, 0.79 mmol) in 30% w/w aqueous H₂O₂ (3 mL) was added iodine (10 mg,0.04 mmol) and the mixture stirred at room temperature overnight. After16 h, the mixture was diluted with water, sonicated, and the resultingsolids were filtered off. The solids were washed with water, then withaqueous Na₂S₂O₃, and dried on a vacuum line to provide crude3-amino-6-chloro-2-fluorophenol (66 mg, 52% yield) which was usedwithout further purification.

-   -   To a solution of crude 3-amino-6-chloro-2-fluorophenol (66 mg,        0.40 mmol) in DMSO (1.3 mL) was added (S)-tert-butyl        3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate        (150 mg, 0.40 mmol) followed by potassium carbonate (139 mg,        1.01 mmol), and the mixture was stirred overnight in an oil bath        heated to 130° C. After 16 h, the mixture was diluted with H₂O        and EtOAc, and the phases were separated. The organic extract        was washed with 1N NaOH, then with saturated aqueous NaCl        solution, dried over anhydrous MgSO₄, filtered and concentrated        in vacuo to provide the title compound (200 mg, 96% yield),        which was used in the next step without further purification.        LCMS (ESI) [M+H]⁺=515.1.

Step 3: (S)-tert-Butyl3-((4-(2-(6-chloro-3-(2-chlorophenylsulfonamido)-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-6-chloro-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.10 mmol) in DCM (0.32 mL) was added 2-chlorobenzenesulfonylchloride (41 mg, 0.19 mmol) followed by addition of pyridine(0.12 mL, 1.46 mmol) and the mixture was stirred at room temperature.After 2 h, the volatiles were removed under reduced pressure, and thecrude residue was directly purified by C18 reverse phase flashchromatography (60-75% ACN/10 mM aqueous ammonium formate, pH=3.8). Theproduct-containing fractions were combined and concentrated to removemost of the ACN. The residue was then diluted with EtOAc and saturatedaqueous NaHCO₃, and the phases were separated. The organic extract waswashed with saturated aqueous NaCl solution, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to provide the title compound(17 mg, 25% yield). LCMS (ESI) [M+H]⁺=689.0.

Step 4:(S)-2-Chloro-N-(4-chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(6-chloro-3-(2-chlorophenylsulfonamido)-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(17 mg, 0.02 mmol) in 1,4-dioxane (0.31 mL) was added 4N HCl in dioxane(0.6 mL, 2.4 mmol) and the mixture was stirred at room temperature.After 2 h, the mixture was diluted with diethyl ether and the resultingsolids were filtered off, washed with diethyl ether, dissolved in amixture of ACN and H₂O and lyophilized to provide the title product (15mg, 97% yield) as a white solid.

Example 20(S)—N-(4-Chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide(Compound 138) Step 1: (S)-tert-Butyl3-((4-(2-(6-chloro-2-fluoro-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-6-chloro-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.10 mmol) in DCM (0.32 mL) was added phenylmethanesulfonylchloride (37 mg, 0.19 mmol) followed by addition of pyridine (0.12 mL,1.46 mmol), and the mixture was stirred at room temperature. After 2 h,the volatiles were removed on a rotovap and the crude residue purifiedby C18 reverse phase flash chromatography (55-75% ACN/10 mM aqueousammonium formate, pH=3.8). The product-containing fractions werecombined and concentrated to remove most of the ACN. The residue wasthen diluted with EtOAc and saturated aqueous NaHCO₃, and the phaseswere separated. The organic extracts were washed with saturated aqueousNaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to provide the title compound (12 mg, 18% yield). LCMS (ESI)[M+H]⁺=669.1.

Step 2:(S)—N-(4-Chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

To a solution of (S)-tert-butyl3-((4-(2-(6-chloro-2-fluoro-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(12 mg, 0.02 mmol) in 1,4-dioxane (0.31 mL) was added 4N HCl in dioxane(0.6 mL, 2.4 mmol) and the mixture stirred at room temperature. After 2h, the mixture was diluted with Diethyl ether, and the resulting solidswere filtered off to provide the crude product which was furtherpurified by C18 reverse phase flash chromatography (20-60% ACN/10 mMaqueous ammonium bicarbonate, pH=10). The product-containing fractionswere combined and lyophilized to provide the title product (8 mg, 81%yield) as a white solid.

Example 21(S)-2-Chloro-N-(2-methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 139) Step 1: (S)-tert-Butyl3-((4-(2-(3-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

-   -   A flask containing a solution of (S)-tert-butyl        3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate        (290 mg, 0.58 mmol), 3-amino-2-methylphenol (79 mg, 0.64 mmol),        and cesium carbonate (401 mg, 1.22 mmol) in DMSO (2.59 mL) was        placed in an oil bath heated to 120° C. and sealed. After 1 h,        the mixture was diluted with EtOAc (75 mL), washed with H₂O (10        mL), then with saturated aqueous NaCl (10 mL), dried over MgSO₄,        filtered and concentrated in vacuo. The resulting crude material        was purified by silica flash column chromatography (0-100% ethyl        acetate/DCM) to provide the title compound (291 mg, quant,        yield) as a pale yellow solid. LCMS (ESI) [M+H]⁺=477.1.

Step 2: (S)-tert-Butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of (S)-tert-butyl3-((4-(2-(3-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(58 mg, 0.12 mmol) in DCM (0.5 mL) was added2-chlorobenzenesulfonylchloride (41 mg, 0.19 mmol) and pyridine (0.15mL) The reaction mixture was stirred at room temperature. After 16 h,the mixture was diluted with EtOAc and saturated aqueous NaHCO₃, and thephases were separated. The organic extracts were washed with saturatedaqueous NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude material thus obtained was purified by silica flashcolumn chromatography (0-100% EtOAc/DCM) to provide the title compound(42 mg, 53% yield). LCMS (ESI) [M+H]⁺=651.1.

Step 3:(S)-2-Chloro-N-(2-methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(42 mg, 0.06 mmol) in 1,4-dioxane (1 mL) was added 4N HCl in dioxane(1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature.After 2 h, the resulting solids were filtered off, washed with1,4-dioxane, then with diethyl ether, dissolved in a mixture of ACN andH₂O and lyophilized to provide the title product (32 mg, 84% yield) asan off-white solid.

Example 22(S)—N-(2-Methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride (Compound 140) Step 1: (S)-tert-Butyl3-((4-(2-(2-methyl-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of (S)-tert-butyl3-((4-(2-(3-amino-2-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(58 mg, 0.12 mmol) in DCM (0.58 mL) was added2-phenylmethanesulfonylchloride (35 mg, 0.18 mmol) and pyridine (0.15mL), and the mixture was stirred at room temperature. After 16 h, afurther portion of phenylmethanesulfonylchloride (105 mg, 0.54 mmol) wasadded and stirring continued at room temperature. After a further 18 h,the mixture was diluted with EtOAc and saturated aqueous NaHCO₃, and thephases were separated. The organic extract was washed with saturatedaqueous NaCl solution, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude material thus obtained was purified bysilica flash column chromatography (0-100% EtOAc/DCM) followed byadditional purification by C18 reverse phase flash chromatography(40-80% ACN/10 mM aqueous ammonium formate). The product-containingfractions were combined and lyophilized to provide the title compound(12 mg, 16% yield). LCMS (ESI) [M+H]⁺=631.1.

Step 2:(S)—N-(2-Methyl-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(2-methyl-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(12 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was added 4N HCl in dioxane(0.29 mL, 1.2 mmol) and the mixture stirred at room temperature. After 2h, the resulting solids were filtered off, washed with 1,4-dioxane, thenwith Diethyl ether, dissolved in a mixture of ACN and H₂O andlyophilized to provide the title product (11 mg, 99% yield) as a whitesolid.

Example 23(S)-2-Chloro-N-(2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride (Compound 141) Step 1: 3-Amino-2-fluorophenol

A solution of 3-amino-2-fluorophenol (100 mg, 0.64 mmol) in EtOAc (3 mL)was added to a N₂ flushed flask containing 10% w/w Pd/C (36 mg). Theflask was purged with H₂ and stirred under a balloon of H₂ at roomtemperature overnight. After 4 h, the flask was purged with N₂ and thesolution was filtered through celite using EtOAc (40 mL) to wash/elute.Concentration in vacuo provided the title compound (63 mg, 78% yield) asa cream colored solid which was used in the next step without furtherpurification. LCMS (ESI) [M+H]⁺=128.6. ¹H NMR (400 MHz, d6-DMSO) δ 9.29(s, 1H), 6.59 (td, J=8.0, 1.7 Hz, 1H), 6.17 (td, J=8.0, 1.6 Hz, 1H),6.09 (td, J=8.0, 1.6 Hz, 1H), 4.94 (s, 2H).

Step 2: (S)-tert-Butyl3-((4-(2-(3-amino-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A flask containing a solution of (S)-tert-butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(175 mg, 0.47 mmol), 3-amino-2-fluorophenol (65 mg, 0.52 mmol), andcesium carbonate (323 mg, 0.98 mmol) in DMSO (2 mL) was placed in an oilbath heated to 120° C. and sealed. After 90 min, the mixture was dilutedwith EtOAc (75 mL), washed with H₂O (10 mL), then with 50% saturatedaqueous NaCl, dried over anhydrous Na₂SO₄, filtered through celite andconcentrated in vacuo to provide the title compound (180 mg, 80% yield)as a brown wax which was used in the next step without furtherpurification. LCMS (ESI) [M+H]⁺=481.0.

Step 3: (S)-tert-Butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.10 mmol) in a mixture of DCM (5 mL) and pyridine (1 mL) wasadded 2-chlorobenzenesulfonylchloride (55 mg, 0.26 mmol) and the mixturestirred at room temperature. After 3 h, a further portion of2-chlorobenzenesulfonylchloride (55 mg, 0.26 mmol) in DCM (1 mL) wasadded followed by continued stirring at room temperature. After afurther 3 h, the mixture was diluted with DCM (50 mL), washed withsaturated NaHCO₃ (10 mL), dried over anydrous Na₂SO₄), filtered andconcentrated in vacuo. The crude material was then purified by silicaflash chromatography (0-100% EtOAc/hexanes) to provide the titlecompound (22 mg, 32% yield) as a clear wax. LCMS (ESI) [M+H]⁺=656.2.

Step 4:(S)-2-Chloro-N-(2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)benzenesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(3-(2-chlorophenylsulfonamido)-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(19 mg, 0.03 mmol) in EtOAc (2 mL) was added 4N HCl in dioxane (2.0 mL,8.0 mmol) and the mixture stirred at room temperature. After 18 h,volatiles were removed under reduced pressure and the crude HCl saltresidue was washed with EtOAc (3×3 mL), then ACN (3×3 mL). The cruderesidue was then sonicated with ACN (3 mL) to produce a suspension andvolatiles removed under reduced pressure (process repeated×3) and theresulting solids dissolved in a mixture of H₂O and ACN and lyophilizedto provide the title product (11 mg, 64% yield) as a white solid.

Example 24(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride (Compound 142) Step 1: (S)-tert-Butyl3-((4-(2-(2-fluoro-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(45 mg, 0.09 mmol) in a mixture of DCM (5 mL) and pyridine (1 mL) wasadded a solution of phenylmethanesulfonyl chloride (45 mg, 0.23 mmol) inDCM (1 mL) and the mixture stirred at room temperature. After 3 h, themixture was diluted with DCM (50 mL), washed with saturated aqueousNaHCO₃ solution (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude material was then purified by silicaflash chromatography (0-100% EtOAc/hexanes) to provide the titlecompound (19 mg, 32% yield) as a clear wax. LCMS (ESI) [M+H]⁺=635.3.

Step 2:(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(2-fluoro-3-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(20 mg, 0.03 mmol) in EtOAc (2 mL) was added 4N HCl in dioxane (2.0 mL,8.0 mmol) and the mixture stirred at room temperature. After 18 h, thevolatiles were removed under reduced pressure and the crude HCl saltresidue was washed with EtOAc (3×3 mL) and then acetonitrile (3×3 mL).The crude residue was then sonicated with ACN (3 mL) to produce asuspension, and the volatiles were removed under reduced pressure(process repeated×3). The resulting solids were dissolved in a mixtureof H₂O and ACN and lyophilized to provide the title product (11 mg, 61%yield) as a white solid.

Example 25(S)—N-(4-Chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride (Compound 143) Step 1: (S)-tert-Butyl3-((4-(2-(6-chloro-2-fluoro-3-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-6-chloro-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.10 mmol) in DCM (0.5 mL) was added 1-propanesulfonyl chloride(21 mg, 0.15 mmol) followed by addition of pyridine (0.12 mL, 1.46 mmol)and the mixture stirred at room temperature. After 16 h, a furtherportion of 1-propanesulfonyl chloride (21 mg, 0.15 mmol) was added andstirring continued at room temperature. After a further 16 h, themixture was diluted with EtOAc and washed with saturated aqueous NaHCO₃,then saturated aqueous NaCl, then with saturated aqueous NH₄Cl solution.The organic extract was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The resulting crude residue thus obtained waspurified by silica flash column chromatography (0-100% EtOAc/DCM)followed by additional purification by reverse phase prep-HPLC (CSHcolumn, 50-70% ACN/10 mM aqueous ammonium formate, pH=3.8). Appropriatefractions were combined and lyophilized to provide the title compound(14 mg, 23% yield). LCMS (ESI) [M+H]⁺=621.1.

Step 2:(S)—N-(4-Chloro-2-fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(6-chloro-2-fluoro-3-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(14 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was added 4N HCl in dioxanes(0.35 mL, 1.4 mmol) and the mixture stirred at room temperature. After 4h, the resulting solids were filtered off, washed with 1,4-dioxane, thenwith Diethyl ether, dissolved in a mixture of ACN and H₂O andlyophilized to provide the title product (10 mg, 80% yield) as a whitesolid.

Example 26(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride (Compound 144) Step 1: (S)-tert-Butyl3-((4-(2-(2-fluoro-3-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of crude (S)-tert-butyl3-((4-(2-(3-amino-2-fluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(45 mg, 0.09 mmol) in a mixture of DCM (5 mL) and pyridine (1 mL) wasadded a solution of 1-propanesulfonyl chloride (33 mg, 0.23 mmol) in DCM(1 mL) and the mixture stirred at room temperature. After 16 h, afurther portion of 1-propanesulfonyl chloride (33 mg, 0.23 mmol) in DCM(1 mL) was added and stirring continued at room temperature. After afurther 18 h, the mixture was diluted with DCM (50 mL), washed withsaturated NaHCO₃ (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude material was then purified by silicaflash chromatography (0-100% EtOAc/hexanes) to provide the titlecompound (14 mg, 25% yield) as a yellow wax. LCMS (ESI) [M+H]⁺=587.1.

Step 2:(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)propane-1-sulfonamidehydrochloride

To a solution of (S)-tert-butyl3-((4-(2-(2-fluoro-3-(propylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(13 mg, 0.02 mmol) in EtOAc (2 mL) was added 4N HCl in dioxane (1.0 mL,4.0 mmol) and the mixture stirred at room temperature. After 16 h, thevolatiles were removed under reduced pressure and the crude HCl saltresidue was washed with EtOAc (3×3 mL) and then ACN (3 20×3 mL). Thecrude residue was then sonicated with ACN (3 mL) to produce a suspensionand the volatiles removed under reduced pressure (the process wasrepeated×3). The resulting solids were dissolved in a mixture of and ACNand lyophilized to provide the title product (9 mg, 78% yield) as awhite solid.

Example 27(S)-1-Cyclohexyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 145)

Step 1: tert-Butyl(3S)-3-((4-(2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of 4-amino-2,3-difluoro-phenol (1.94 g, 13.4 mmol),tert-butyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(5.00 g, 13.4 mmol) and cesium carbonate (7.42 g, 22.8 mmol) in DMSO (45mL) was stirred at 130° C. for 6 h. LCMS showed complete conversion. Theresulting solution was diluted with water and extracted with ethylacetate. The organic layers were washed twice with brine and dried overanhydrous sodium sulfate. The solvent was concentrated under vacuum. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (20%-50%) to afford the title compound (5.60 g,83.9% yield) as a black solid. LCMS (ESI): [M+H]⁺=499.2.

Step 2: tert-Butyl(3S)-3-((4-(2-(4-(cyclohexylmethylsulfonylamino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of tert-butyl(3S)-3-((4-(2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(400 mg, 0.80 mmol) in chloroform (20 mL) was stirred at 20° C. Then4-methylmorpholine (487 mg, 4.81 mmol) and cyclohexylmethanesulfonylchloride (410 mg, 2.09 mmol) were added followed by stirring at 20° C.for 72 h. The resulting solution was diluted with water and extractedwith DCM. The organic layers were combined and the solvent removed undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (0-35%) to afford the title compound(130 mg, 24.6% yield) as a white solid. LCMS (ESI): [M+H]⁺=659.2.

Step 3:(S)-1-Cyclohexyl-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride

A solution of tert-butyl(3S)-3-((4-(2-(4-(cyclohexylmethylsulfonylamino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(120 mg, 0.18 mmol) in DCM (6 mL) was added 4 M HCl in 1,4-dioxane (2mL) and stirred at 20° C. for 2 h. The solvent was concentrated undervacuum. The crude product was purified by prep-HPLC. The resultingsolution was concentrated under vacuum and diluted with 1 M HCl in water(3 mL). Then the product was concentrated under vacuum to afford thetitle compound (45.1 mg, 42.6% yield) as a white solid.

Example 28(S)—N-(2,3-Difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)cyclopropanecarboxamidehydrochloride (Compound 147)

Step 1: (S)-tert-Butyl3-(4-(2-(4-(cyclopropanecarboxamido)-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-((4-(2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(400 mg, 0.80 mmol) in pyridine (4 mL) was added cyclopropanecarbonylchloride (0.11 mL, 1.22 mmol) and the solution was stirred for 16 h atroom temperature. The mixture was evaporated under vacuum. The residuewas purified by prep-HPLC to afford the title compound (365 mg, 80.3%yield) as a pink solid. LCMS (ESI): [M+H]⁺=567.2.

Step 2:(S)—N-(2,3-difluoro-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)cyclopropanecarboxamidehydrochloride

To a solution of tert-butyl(3S)-3-((4-(2-(4-(cyclopropanecarbonylamino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(365 mg, 0.64 mmol) in DCM (4 mL) was added 4 M hydrogen chloride in1,4-dioxane (1 mL). The mixture was stirred for 2 h at room temperature.The crude product was purified by prep-HPLC. The resulting solution wasconcentrated under vacuum and diluted with 1 M HCl in water (3 mL). Theproduct was then concentrated under vacuum to afford the title compound(25.2 mg, 7.8% yield) as a light yellow solid.

Example 29N-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)spiro[2.2]pentane-1-carboxamidehydrochloride (Compound 150)

Step 1: tert-Butyl(3S)-3-((4-(2-(2,3-difluoro-4-(spiro[2.2]pentane-1-carboxamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylateand tert-butyl(3S)-3-((4-(2-(2,3-difluoro-4-(spiro[2.2]pentane-1-carboxamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of spiro[2.2]pentane-2-carboxylic acid (450 mg, 4.01 mmol)in 1,2-DCM (5 mL) was added a drop of DMF. Then ethanedioyl dichloride(509 mg, 4.01 mmol) was added at 0° C. followed by stirring at 0° C. for30 min. The cold solution was then added to a solution of tert-butyl(3S)-3-[[4-[2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(400 mg, 0.800 mmol) in pyridine (4 mL) followed by stirring at 25° C.for 1 h. The resulting solution was diluted with water and extractedwith DCM. The organic layer was washed with brine and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (0-30%). The crude product wasfurther purified by prep-HPLC and chiral HPLC separation to provide twosingle stereoisomers stereogenic at the 2 position of the amide(conditions: Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile PhaseA:MTBE-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 2B to 2 B in 12 min; 254/220 nm).

tert-Butyl(3S)-3-((4-(2-(2,3-difluoro-4-(spiro[2.2]pentane-1-carboxamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 1, 50 mg, 13.7% yield). LCMS (ESI): [M+H]⁺=593.2; (rt=2.044 min,Chiral IA, 0.46×5 cm; 3 um, MTBE (0.1% DEA):IPA=98:2, 1.0 ml/min)

tert-Butyl(3S)-3-((4-(2-(2,3-difluoro-4-(spiro[2.2]pentane-1-carboxamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 2, 50 mg, 13.7% yield). LCMS (ESI): [M+H]⁺=593.2; (rt=2.513 min,chiral IA, 0.46×5 cm; 3 um, MTBE (0.1% DEA):IPA=98:2, 1.0 ml/min)

Step 2:N-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)spiro[2.2]pentane-1-carboxamidehydrochloride

To a solution of tert-butyl(3S)-3-[[4-[2-[2,3-difluoro-4-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(50 mg, 0.080 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (1mL) followed by stirring at 20° C. for 1 h. The solvent was concentratedunder vacuum. The residue was purified by Prep-HPLC to afford the titleproduct (18.1 mg, 41%) as a white solid. The absolute stereochemistry ofthe amide wasn't determined.

Example 30(S)-1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 153)

Step 1: 1-(Benzyloxy)-2,3,5-trifluoro-4-nitrobenzene

A mixture of 2,3,4,6-tetrafluoronitrobenzene (3.00 g, 15.4 mmol), benzylalcohol (1.27 mL, 12.3 mmol) and tetrabutylammonium hydrogen sulfate(0.522 g, 1.54 mmol) in DCM (75 mL) was added to a solution of sodiumhydroxide (0.615 g, 15.4 mmol) in water (75 mL). The mixture was stirredfor 18 h at room temperature. The reaction was quenched with water. Theresulting solution was extracted with DCM, and the solvent wasconcentrated under vacuum. The residue was purified by silica flashchromatography eluting with DCM/petroleum ether (1/20) to afford thetitle compound (1.68 g, 38.6% yield) as a light yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.43 (m, 6H), 5.24 (s, 2H).

Step 2: 4-Amino-2,3,5-trifluorophenol

Under hydrogen, a mixture of 1-benzyloxy-2,3,5-trifluoro-4-nitro-benzene(880 mg, 3.11 mmol) and 10% Pd/C (220 mg) in methyl alcohol (30 mL) wasstirred for 3 h at room temperature. Acetic acid (1 mL) was added to themixture. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica flash chromatographyeluting with methanol/DCM (1:20) to afford the title compound (210 mg,41.4% yield) as a brown solid. LCMS (ESI): [M+H]⁺=164.2.

Step 3:(S)-tert-Butyl3-(4-(2-(4-amino-2,3,5-trifluorophenoxy)pyridin-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate

Under nitrogen, to a solution of 4-amino-2,3,5-trifluoro-phenol (200 mg,1.07 mmol) and tert-butyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(398 mg, 1.07 mmol) in DMSO (5 mL) was added cesium carbonate (590.9 mg,1.81 mmol) followed by stirring for 16 h at 130° C. The resultingsolution was quenched with water and extracted with ethyl acetate. Theorganic layers were combined. The organic extract was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (1:1) to afford the title compound (180 mg,32.7% yield) as a brown solid. LCMS (ESI): [M+H]⁺=517.2.

Step 4: (S)-tert-Butyl3-(4-(2-(2,3,5-trifluoro-4-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate

To a solution of alpha-toluenesulfonylchloride (221 mg, 1.16 mmol) andtert-butyl(3S)-3-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(150 mg, 0.29 mmol) in pyridine (4 mL) was added 4-dimethylaminopyridine(71 mg, 0.58 mmol). The mixture was stirred for 16 h at roomtemperature. The solvent was concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (1:1) to afford the title compound (96 mg, 49.3%yield) as a brown solid. LCMS (ESI): [M+H]⁺=671.2.

Step 5:(S)-1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride

To a solution of tert-butyl(3S)-3-((4-(2-(4-(benzylsulfonylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(86 mg, 0.13 mmol) in DCM (4 mL) was added 4 M HCl in 1,4-dioxane (1 mL)followed by stirring at room temperature for 1 h. The solvent wasremoved under vacuum. The residue was purified by prep-HPLC to affordthe title compound (24 mg, 30.8% yield) as a yellow.

Example 31(S)—N-(2,6-Difluoro-3-methyl-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)(phenyl)methanesulfonamidehydrochloride

Step 1: 2-Bromo-1,3,5-trifluoro-4-nitro-benzene

To 1-bromo-2,4,6-trifluorobenzene (10 g, 47.4 mmol) was successivelyadded a mixture of sulfuric acid (10 mL) and nitric acid (10 mL) at 0°C. The solution was stirred for 1 h at this temperature. TLC (petroleumether/ethyl acetate=20/1, Rf=0.25) indicated the reaction was completed.The reaction was quenched with water and extracted with DCM. Thecombined organic extract was washed with water, saturated sodiumbicarbonate solution, and brine and dried over anhydrous sodium sulfate.The solvent was removed under vacuum to afford the title compound (8.0g, 65.9% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.03 (m, 1H).

Step 2: 1-(Benzyloxy)-2-bromo-3,5-difluoro-4-nitrobenzene

A mixture of 2-bromo-1,3,5-trifluoro-4-nitro-benzene (8.0 g, 31.3 mmol),benzyl alcohol (3.38 g, 31.3 mmol), 2 M sodium hydroxide solution (16mL, 32 mmol), tetrabutylammonium hydrogen sulfate (1.17 g, 3.44 mmol) inDCM (30 mL) was stirred for 16 h at room temperature. TLC (10% ethylacetate in petroleum ether, Rf=0.5) indicated the reaction wascompleted. The reaction was quenched with water and extracted with DCM.The organic extracts were combined, washed with water, brine, and driedover anhydrous sodium sulfate. The solvent was removed under vacuum togive the title compound (9.2 g, 85.5% yield) as a yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.30-7.20 (m, 5H), 6.90-6.70 (m, 1H), 5.30-5.20 (m,2H).

Step 3: 1-Benzyloxy-3,5-difluoro-2-methyl-4-nitro-benzene

Under nitrogen, a mixture of1-benzyloxy-2-bromo-3,5-difluoro-4-nitro-benzene (3.5 g, 10.2 mmol),trimethylboroxide (3.49 mL, 12.2 mmol), potassium carbonate (4.2 g, 30.5mmol) and tetrakis(triphenylphosphine) palladium (1.1 g, 1.02 mmol) intoluene (40 mL) and water (10 mL) was stirred at 90° C. for 16 h. Thesolvent was removed under vacuum. The residue was purified by silicaflash chromatography eluting with DCM/petroleum ether (0-100%) to affordthe title compound (1.3 g, 38.4% yield) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.20 (m, 5H), 6.65-6.55 (m, 1H), 5.30-5.20 (m, 2H),2.20 (s, 3H).

Step 4: 4-Amino-3,5-difluoro-2-methyl-phenol

A mixture of 1-benzyloxy-3,5-difluoro-2-methyl-4-nitro-benzene (900 mg,3.22 mmol) and 20% palladium on activated carbon (300 mg) in methylalcohol (15 mL) was stirred for 16 h at room temperature under hydrogen.The reaction was quenched with acetic acid (1 mL). The solids werefiltered out and the solvent was removed under vacuum. The residue waspurified by silica flash chromatography (DCM/petroleum ether 0-100%) toafford the title compound (240 mg, 46.8% yield) as a light yellow solid.LCMS (ESI): [M+H]⁺=160.1.

Step 5:(S)—N-(2,6-Difluoro-3-methyl-4-(3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)(phenyl)methanesulfonamidehydrochloride

The title compound was prepared according to Example 27. This providesthe title compound (47.8 mg, 0.079 mmol, 73.4%) as a white solid.

Example 32(S)—N-(2,3-Difluoro-5-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

Step 1: 6-Bromo-2,3-difluoro-4-nitro-phenol

A solution of 6-bromo-2,3-difluorophenol (2.0 g, 9.57 mmol) in DCM (8mL) was cooled to −10° C., and then a mixture of nitric acid (0.61 mL,9.57 mmol) and sulfuric acid (4 mL) was added dropwise. The resultingmixture was stirred at −10° C. for 1 h. The mixture was poured intoice/water, extracted with ethyl acetate, and then washed with water andbrine. The organic extract was concentrated in vacuum. The residue waspurified by silica flash chromatography (petroleum ether/ethyl acetate20:1) to provide the title compound (1.8 g, 74.1% yield) as a yellowsolid. LCMS (ESI): [M+H]⁺=252.1.

Step 2: 2-Benzyloxy-1-bromo-3,4-difluoro-5-nitro-benzene

A mixture of 6-bromo-2,3-difluoro-4-nitro-phenol (1.8 g, 7.09 mmol),benzyl bromide (1.74 mL, 14.6 mmol), potassium carbonate (2.96 g, 21.4mmol) in DMF (20 mL) was stirred for 16 h at room temperature. Thereaction was quenched with water and extracted with ethyl acetate. Thecombined organic extract was washed with brine, concentrated andpurified by silica flash chromatography eluting with DCM/petroleum ether(0-100%) to afford the title compound (2.3 g, 94.3% yield) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (s, 1H), 7.55-7.30 (m, 5H),5.36-5.10 (m, 2H).

Step 3: 2-Benzyloxy-3,4-difluoro-1-methyl-5-nitro-benzene

Under nitrogen, a mixture of2-benzyloxy-1-bromo-3,4-difluoro-5-nitro-benzene (2.2 g, 6.39 mmol),trimethylboroxine (2.19 mL, 7.67 mmol), potassium fluoride (1.1 g, 19.31mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichlorideDCM complex (522 mg, 0.64 mmol) in toluene (40 mL) and water (8 mL) wasstirred at 90° C. for 16 h. The solvent was removed under vacuum. Theresidue was purified by silica flash chromatography (DCM/petroleum ether0-100%) to afford the title compound (900 mg, 50.4% yield) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (m, 1H), 7.46-7.43 (m, 5H), 5.33(s, 2H), 2.33 (s, 3H).

Step 4: 4-Amino-2,3-difluoro-6-methyl-phenol

Under hydrogen, a mixture of2-benzyloxy-3,4-difluoro-1-methyl-5-nitro-benzene (800 mg, 2.86 mmol)and 10% palladium on activated carbon (240 mg) in methyl alcohol (25 mL)was stirred for 2 h at room temperature. The reaction was quenched withacetic acid (1 mL) and the solids were filtered out. The solvent wasconcentrated under vacuum. The residue was purified by silica flashchromatography (DCM/petroleum ether 0-100%) to afford the title compound(250 mg, 54.8% yield) as a light yellow solid. LCMS (ESI): [M+H]⁺=160.1.

Step 5:N-(2,3-Difluoro-5-methyl-4-((3-(2-(((3S)-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide

The title compound was prepared according to Example 27 to provide thetitle compound (50 mg, 36.2% yield) as a white solid.

Example 33(S)—N-(2,3-Difluoro-6-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

Step 1: (4-Amino-2,3-difluoro-phenyl) acetate

To a solution of 4-amino-2,3-difluoro-phenol (4.0 g, 27.6 mmol) inpyridine (50 mL) was added acetic anhydride (2.59 mL, 27.6 mmol) at 0°C. and the mixture was stirred for 16 h at room temperature. The mixturewas concentrated and purified by silica flash chromatography (ethylacetate/petroleum ether 0-100%) to afford the title compound (3.3 g, 64%yield) as a brown solid.

Step 2: (4-Amino-5-bromo-2,3-difluoro-phenyl) acetate

To a solution of (4-amino-2,3-difluoro-phenyl) acetate (1.67 g, 5.62mmol) in DMF (30 mL) was added 1-bromo-2,5-pyrrolidinedione (1.1 g, 6.19mmol) at 0° C. and the mixture was stirred for 16 h at room temperature.The mixture was concentrated and purified by silica flash chromatography(ethyl acetate/petroleum ether 0-100%) to afford the title compound (1.0g, 66.9% yield) as a brown solid. LCMS (ESI): [M+H]⁺=265.9.

Step 3: tert-Butyl acetyl(6-bromo-2,3-difluoro-4-hydroxyphenyl)carbamate

A mixture of (4-amino-5-bromo-2,3-difluoro-phenyl) acetate (2.0 g, 7.52mmol), di-tert-butyldicarbonate (2.0 g, 9.16 mmol),4-dimethylaminopyridine (100.0 mg, 0.82 mmol) in THF (20 mL) was stirredfor 3 h at room temperature. The mixture was concentrated and purifiedby silica flash chromatography (ethyl acetate/petroleum ether 0-20%) toafford the title compound (900 mg, 32.7% yield) as a yellow solid. LCMS(ESI): (M+42)⁺=409.1.

Step 4: tert-Butylacetyl(2,3-difluoro-4-hydroxy-6-methylphenyl)carbamate

Under nitrogen, a mixture of tert-butylacetyl(6-bromo-2,3-difluoro-4-hydroxyphenyl)carbamate (1.0 g, 2.73mmol), trimethylboroxine (2.5 mL, 8.73 mmol),bis(triphenylphosphine)palladium(II) chloride (193 mg, 0.28 mmol), andsodium bicarbonate (678 mg, 8.07 mmol) in 1,2-dimethoxyethane (30 mL)was stirred at 75° C. for 16 h. The reaction was diluted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate,concentrated in vacuo and purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (0-40%) to afford the titlecompound (670 mg, 81.4% yield) as a light yellow oil. LCMS (ESI):[M+H]⁺=302.1.

Step 5: 4-Amino-2,3-difluoro-5-methyl-phenol

To a suspension of tert-butylacetyl(2,3-difluoro-4-hydroxy-6-methylphenyl)carbamate (530 mg, 1.76mmol) in methyl alcohol (10 mL) was added boron trifluoride diethyletherate (10.0 mL, 81.03 mmol) and the mixture was stirred for 24 h at75° C. The mixture was diluted with ethyl acetate and washed with water.The organic layer was concentrated in vacuo. The residue was purified bysilica flash chromatography (methanol/DCM (0-20%) to afford the titlecompound (130 mg, 46.4% yield) as a purple solid. LCMS (ESI):[M+H]⁺=160.1.

Step 6:(S)—N-(2,3-Difluoro-6-methyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

The title compound was prepared according to Example 27 to provide thetitle compound (23.9 mg, 18.7% yield) as a white solid.

Example 34(S)—N-(2-Chloro-3-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide(Compound 161)

Step 1: 4-Bromo-3-chloro-2-fluorophenol

Under nitrogen, a solution of 1-bromo-2-chloro-3-fluoro-4-iodo-benzene(1.50 g, 4.47 mmol), potassium hydroxide (1.00 g, 17.89 mmol),1,10-phenanthroline (0.32 g, 1.79 mmol), copper iodide (0.17 g, 0.89mmol) in water (20 mL) and DMSO (20 mL) was stirred overnight at 100° C.2 M HCl (50 mL) was then added and the solids was filtered out. Theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine and removed in vacuo. The residue was purified bysilica flash chromatography (petroleum ether/ethyl acetate 10:1) toafford the title compound (300 mg, 29.7% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 10.65 (s, 1H), 7.40 (dd, J=9.0, 2.1 Hz, 1H), 6.93 (t, 7=8.8Hz, 1H).

Step 2: tert-Butyl(3S)-3-((4-(2-(4-bromo-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of tert-butyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(795 mg, 2.13 mmol), 4-bromo-3-chloro-2-fluoro-phenol (600 mg, 2.66mmol), potassium carbonate (734 mg, 5.32 mmol) inl-methyl-2-pyrrolidinone (20 mL) was stirred for 16 h at 100° C. Thereaction was quenched with water and extracted with ethyl acetate. Thecombined organic extracts were washed with brine and the solvent wasremoved. The residue was purified by silica flash chromatography(petroleum ether/ethyl acetate 1:1) to afford the title compound (1.0 g,46.1% yield). LCMS (ESI): [M+H]⁺=580.2.

Step 3: tert-Butyl(3S)-3-((4-(2-(4-(benzhydrylideneamino)-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of tert-butyl(3S)-3-((4-(2-(4-bromo-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(200 mg, 0.21 mmol), benzophenone imine (34 mg, 0.19 mmol),bis(dibenzylideneacetone)palladium(II) (19 mg, 0.02 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg, 0.04 mmol),sodium tert-butoxide (40 mg, 0.41 mmol) in toluene (5 mL) was stirredfor 2 h at 100° C. The solvent was removed and the residue was purifiedby silica flash chromatography (petroleum ether/ethyl acetate (1:1) toafford the title compound (180 mg, 76.7% yield). LCMS (ESI):[M+H]⁺=679.1.

Step 4: tert-Butyl(3S)-3-((4-(2-(4-amino-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-((4-(2-(4-(benzhydrylideneamino)-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(200 mg, 0.29 mmol) in THF (10 mL) and water (10 mL) was added aceticacid (1 mL). The reaction mixture was stirred for 3 h at 35° C. Thesolvent was removed in vacuo. The residue was purified by silica flashchromatography (petroleum ether/ethyl acetate 1:1) to afford the titlecompound (110 mg, 72.5% yield). LCMS (ESI): [M+H]⁺=515.2.

Step 5:N-(2-Chloro-3-fluoro-4-((3-(2-(((3S)-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide

To a solution of tert-butyl(3S)-3-((4-(2-(4-amino-3-chloro-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(150 mg, 0.29 mmol) in DCM (15 mL) was added pyridine (0.23 mL) andalpha-toluenesulfonylchloride (83 mg, 0.44 mmol). The solution wasstirred for 2 h at 20° C. Then the reaction was quenched with water andextracted with DCM. The solvent was removed and the crude product wasdissolved in DCM (4 mL). Then 4 M HCl in 1,4-dioxane (1 mL) was added.The reaction was stirred for 2 h at room temperature. The solvent wasremoved and the residue was further purified by prep-HPLC to give thetitle compound (29.2 mg, 17.6% yield) as a light yellow solid.

Example 35(S)—N-(2-Cyano-3-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

Step 1: 1-(Benzyloxy)-3-bromo-2-fluoro-4-nitrobenzene

To a solution of 3-bromo-1,2-difluoro-4-nitro-benzene (5 g, 21.1 mmol),tetrabutyl-ammonium hydrogen sulfate (720 mg, 2.1 mmol) andphenylmethanol (2.5 g, 23.1 mmol) in DCM (100 mL) was added 1 M sodiumhydroxide solution (20 ml) dropwise. The mixture was stirred at 25° C.for 1.5 h and subsequently diluted with water. The resulting solutionwas extracted with ethyl acetate and the organic layers were combined.The organic extract was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica flashchromatography eluting (ethyl acetate/petroleum ether (1:4)) to affordthe title compound (6.5 g, 90.1% yield) as a yellow solid. ¹H NMR (300MHz, CD₃OD) δ 7.86 (dd, J=9.2, 2.1 Hz, 1H), 7.51-0.28 (m, 6H), 5.29 (s,2H).

Step 2: 3-(Benzyloxy)-2-fluoro-6-nitrobenzonitrile

Under nitrogen, a mixture of1-benzyloxy-3-bromo-2-fluoro-4-nitro-benzene (2.0 g, 6.13 mmol),copper(I) cyanide (1.1 g, 12.27 mmol) in N,N-dimethylacetamide (40 mL)was stirred at 130° C. for 2 h. The reaction mixture was diluted withwater and extracted with ethyl acetate followed by combination oforganic layers. The organic extract was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography (ethyl acetate/petroleum ether) to affordthe title compound (1.1 g, 64.6% yield) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.31 (dd, J=9.3, 1.6 Hz, 1H), 7.80 (dd, J=9.4, 8.5Hz, 1H), 7.54-7.46 (m, 2H), 7.48-7.40 (m, 2H), 7.44-7.35 (m, 1H), 5.43(s, 2H).

Step 3: 6-Amino-2-fluoro-3-hydroxybenzonitrile

Under hydrogen, a mixture of 3-benzyloxy-2-fluoro-6-nitro-benzonitrile(1.2 g, 4.19 mmol) and 10% Pd/C (500 mg) in ethyl acetate (70 mL) wasstirred at 25° C. for 2 h. The mixture was filtered, and the organiclayer was concentrated under vacuum. The residue was purified by silicaflash chromatography eluting (ethyl acetate/petroleum ether 7:3) toafford the title compound (500 mg, 74.6% yield) as an off-white solid.LCMS (ESI): [M+H]⁺=153.0.

Step 4:(S)—N-(2-Cyano-3-fluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamidehydrochloride

The title compound was prepared according to Example 27 to provide thetitle compound (31 mg, 13.6% yield) as a white solid.

Example 36N-(2,6-Difluoro-3-methyl-4-((3-(2-(((3S,5R)-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide(Compound 164)

Step 1: Benzyl(3S,5R)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate

A mixture of 2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine (1.0 g, 4.77mmol), benzyl (3S,5R)-3-amino-5-methyl-piperidine-1-carboxylate (1.24 g,5.01 mmol), N,N-diisopropylethylamine (2.36 mL, 14.31 mmol) and cesiumfluoride (0.867 mg, 5.72 mmol) in DMSO (25 mL) was stirred at 80° C. for2 h. The reaction was quenched with water. The mixture was extractedwith ethyl acetate, washed with water and dried over anhydrous sodiumsulfate followed by concentration under vacuum. The residue was purifiedby silica flash chromatography (petroleum ether/ethyl acetate 1:1) toafford the title compound (662 mg, 32.9% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=422.2.

Step 2: Benzyl(3S,5R)-3-((4-(2-(4-amino-3,5-difluoro-2-methyl-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate

A mixture of 4-amino-3,5-difluoro-2-methyl-phenol (120 mg, 0.75 mmol),benzyl(3S,5R)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate(220 mg, 0.52 mmol), cesium carbonate (676 mg, 2.07 mmol) in DMSO (5 mL)was stirred for 16 h at 80° C. The reaction was quenched with water andextracted with ethyl acetate. The resulting solution was washed withwater, dried over anhydrous magnesium sulfate and concentrated in vacuo.The mixture was concentrated and purified by silica flash chromatography(ethyl acetate/petroleum ether 0-100%) to afford the title compound (260mg, 88.9% yield) as a light yellow solid. LCMS (ESI): [M+H]⁺=561.2.

Step 3: Benzyl(3S,5R)-3-((4-(2-(4-(benzylsulfonylamino)-3,5-difluoro-2-methyl-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate

To a solution of benzyl(3S,5R)-3-((4-(2-(4-amino-3,5-difluoro-2-methyl-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate(240 mg, 0.43 mmol) in pyridine (4 mL) was addedalpha-toluenesulfonylchloride (163 mg, 0.86 mmol). The reaction mixturewas stirred for 16 h. The mixture was concentrated and purified bysilica flash chromatography (ethyl acetate/petroleum ether (0-100%) toafford the title compound (260 mg, 85% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=715.2.

Step 4:N-(2,6-Difluoro-3-methyl-4-((3-(2-(((3S,5R)-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide

To a solution of benzyl(3S,5R)-3-((4-(2-(4-(benzylsulfonylamino)-3,5-difluoro-2-methyl-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-methyl-piperidine-1-carboxylate(260 mg, 0.36 mmol) in DCM (4 mL) was added 33% HBr in acetic acid (2mL). The mixture was stirred for 2 h at room temperature. The mixturewas concentrated in vacuo, and the crude product was purified byprep-HPLC to provide the title compound (22.2 mg, 10.5% yield) as awhite solid.

Example 37(S)—N-(2,3-Difluoro-4-((3-(2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide(Compound 167)

Step 1:2,3-Difluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)aniline

To a mixture of2,3-difluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(500 mg, 1.44 mmol) in DCM (20 mL) was added 3-chloroperoxybenzoicacid(548 mg, 3.18 mmol), and the mixture was stirred for 1 h at roomtemperature. The reaction was quenched with saturated aqueous sodiumbisulfite solution and extracted with ethyl acetate. The organic layerswere combined and washed with brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by silica flashchromatography (petroleum ether/ethyl acetate 15:85). This resulted inthe title compound (370 mg, 67.7% yield) as a yellow solid. LCMS (ESI):[M+H]⁺=379.1.

Step 2: tert-Butyl(3S)-3-((4-(2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

A mixture of2,3-difluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(200 mg, 0.55 mmol), tert-butyl (3S)-3-amino-1-pyrrolidinecarboxylate(205 mg, 1.1 mmol), N,N-diisopropylethylamine (0.29 mL, 1.66 mmol) andcesium fluoride (251 mg, 1.65 mmol) in DMSO (5 mL) was stirred at 80° C.for 2 h. The resulting solution was then diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica flash chromatography eluting (petroleumether/ethyl acetate 3:7) to provide the title compound (120 mg, 44.9%yield) as a yellow solid. LCMS (ESI): [M+H]⁺=485.2.

Step 3: tert-Butyl(3S)-3-((4-(2-(4-(benzylsulfonylamino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-((4-(2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate(100 mg, 0.21 mmol) in DCM (2 mL) was added pyridine (0.5 mL, 6.21 mmol)and alpha-toluenesulfonylchloride (51 mg, 0.27 mmol), and the mixturewas stirred for 2 h at room temperature. The resulting solution wasconcentrated under vacuum. The residue was purified by silica flashchromatography (DCM/methanol 95:5) to provide the title compound (120mg, 91% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=639.2.

Step 4:(S)—N-(2,3-Difluoro-4-((3-(2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

To a mixture of tert-butyl(3S)-3-((4-(2-(4-(benzylsulfonylamino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate(120 mg, 0.19 mmol) in DCM (5 mL) was added 4 M HCl in 1,4-dioxane (0.5mL), and the mixture was stirred for 1 h at room temperature. Thesolvent was removed under vacuum and the crude product purified byprep-HPLC to afford the title compound (28.9 mg, 27.9% yield) as a whitesolid.

Example 38N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3-difluorophenyl)-1-phenylmethanesulfonamide(Compound 169)

Step 1: tert-Butyl((1r,4r)-4-((4-(2-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

Under nitrogen, a solution ofN-(2,3-difluoro-4-((3-(2-methylsulfinylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide(200 mg, 0.39 mmol), tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (83mg, 0.39 mmol), cesium fluoride (141 mg, 0.93 mmol),N,N-diisopropylethylamine (150 mg, 1.16 mmol) in DMSO (10 mL) wasstirred for 16 h at 80° C. The reaction mixture was diluted with waterand extracted with ethyl acetate three times. The combined organicextracts were dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography (ethylacetate/petroleum ether (1:2)) to afford the title compound (190 mg,73.6% yield) as a brown oil. LCMS (ESI): [M+H]⁺=667.3

Step 2:N-(4-((3-(2-(((1r,4r)-4-Aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3-difluorophenyl)-1-phenylmethanesulfonamide

A solution of tert-butyl((1r,4r)-4-((4-(2-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(170 mg, 0.25 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at 15°C. for 0.5 h. The solvent was removed under vacuum and the residuepurified by prep-HPLC to give the title compound (62.8 mg, 41.5% yield)as a white solid.

Example 39(S)—N-(6-Fluoro-2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

Step 1: 2,4-Dibromo-6-fluoro-3-methyl-aniline

To a mixture of 2-fluoro-5-methylaniline (5.9 g, 47.2 mmol) inacetonitrile (200 mL) was added 1-bromo-2,5-pyrrolidinedione (1.68 g,94.3 mmol) at 0° C. The mixture was stirred for 0.5 h at roomtemperature. The solvent was then concentrated under vacuum and purifiedby silica flash chromatography (petroleum ether/ethyl acetate 9:1) toprovide the title compound (1.5 g, 93.7% yield) as a brown solid. LCMS(ESI): [M+H]⁺=283.9.

Step 2:2-Bromo-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of 2,4-dibromo-6-fluoro-3-methyl-aniline (5 g, 17.7 mmol),bis(pinacolato)diboron (3.59 g, 14.1 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.3 g, 1.77mmol) and potassium acetate (5.2 g, 53.0 mmol) in 1,4-dioxane (80 mL)was stirred at 90° C. overnight. The resulting solution was diluted withwater and extracted with ethyl acetate. The organic extract was driedover anhydrous magnesium sulfate and solvent was removed in vacuo. Theresidue was purified by silica flash chromatography (petroleumether/ethyl acetate 93:7) to provide the title compound (2.9 g, 49.7%yield) as a brown oil. LCMS (ESI): [M+H]⁺=330.1.

Step 2: tert-ButylN-(2-bromo-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-tert-butoxycarbonyl-carbamate

A mixture of2-bromo-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1.4 g, 4.24 mmol) and di-tert-butyldicarbonate (2.31 g, 10.61 mmol) inTHF (50 mL) was stirred at 70° C. for 2 h. The organic layer wasconcentrated under vacuum. The residue was purified by silica flashchromatography (petroleum ether/ethyl acetate 92:8) to provide the titlecompound (1.2 g, 53.3% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 7.48 (d, 7=9.4 Hz, 1H), 2.64 (s, 3H), 1.49 (s, 6H), 1.41 (s, 18H).

Step 4: tert-ButylN-(2-bromo-6-fluoro-4-hydroxy-3-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate

To a mixture of tert-butylN-(2-bromo-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-tert-butoxycarbonyl-carbamate(1.9 g, 3.58 mmol) in THF (30 mL) was added 1 M sodium hydroxidesolution (10.75 mL, 10.75 mmol) and 30% hydrogen peroxide (1.2 g, 10.75mmol). The mixture was stirred for 1 h at room temperature and pH wasthen adjusted to pH=7 through addition of acetic acid. The resultingsolution was extracted with ethyl acetate and the combined organiclayers were concentrated in vacuo. The residue was purified by silicaflash chromatography (petroleum ether/ethyl acetate 82:18) to providethe title compound (980 mg, 65.1% yield) as a yellow solid. LCMS (ESI):(M−H)⁻⁼418.1.

Step 5: tert-ButylN-(4-benzyloxy-2-bromo-6-fluoro-3-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate

To a mixture of tert-butylN-(2-bromo-6-fluoro-4-hydroxy-3-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate(980 mg, 2.33 mmol) in DMF (20 mL) were added potassium carbonate (967mg, 7 mmol) and benzyl bromide (479 mg, 2.8 mmol). The mixture wasstirred for 2 h at room temperature, diluted with water and extractedwith ethyl acetate. The organic extract was washed with brine andconcentrated in vacuo. The residue was purified by silica flashchromatography (petroleum ether/ethyl acetate 92:8) to provide the titlecompound (1.1 g, 92.4% yield) as a yellow solid. ¹H NMR (300 MHz, CDCl₃)δ 7.53-7.32 (m, 5H), 6.71 (d, J=11.0 Hz, 1H), 5.07 (s, 2H), 2.37 (s,3H), 1.49 (s, 18H).

Step 6:tert-Butyl-N-(4-benzyloxy-6-fluoro-2,3-dimethyl-phenyl)-N-tert-butoxycarbonyl-carbamate

A mixture oftert-butyl-N-(4-benzyloxy-2-bromo-6-fluoro-3-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate(900 mg, 1.76 mmol), methylboronic acid (317 mg, 5.29 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex(145 mg, 0.18 mmol) and potassium fluoride (307 mg, 5.29 mmol) intoluene (20 mL) and water (4 mL) was stirred at 90° C. for 2 h undernitrogen. The resulting solution was diluted with water, extracted withethyl acetate. The organic extract was concentrated in vacuum. Theresidue was purified by silica flash chromatography eluting withpetroleum ether/ethyl acetate (92:8). This resulted in the titlecompound (700 mg, 89.1% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃)δ 7.52-7.30 (m, 5H), 6.61 (d, J=11.3 Hz, 1H), 5.05 (s, 2H), 2.20 (s,3H), 2.15 (s, 3H), 1.46 (s, 18H).

Step 7: tert-ButylN-tert-butoxycarbonyl-N-(6-fluoro-4-hydroxy-2,3-dimethyl-phenyl)carbamate

To a mixture of tert-butylN-(4-benzyloxy-6-fluoro-2,3-dimethyl-phenyl)-N-tert-butoxycarbonyl-carbamate(700 mg, 1.57 mmol) in methyl alcohol (20 mL) was added 10% Pd/C (300mg), and the mixture was stirred for 2 h at room temperature underhydrogen. The solids were filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicaflash chromatography (petroleum ether/ethyl acetate 84:16) to providethe title compound (500 mg, 89.5% yield) as a white solid. LCMS (ESI):[M−H]⁻=354.1

Step 8: 4-Amino-5-fluoro-2,3-dimethyl-phenol hydrochloride

To a mixture of tert-butylN-tert-butoxycarbonyl-N-(6-fluoro-4-hydroxy-2,3-dimethyl-phenyl)carbamate(580 mg, 1.63 mmol) in DCM (4 mL) was added 4 M HCl in 1,4-dioxane (2mL). The mixture was stirred for 1 h at room temperature andconcentrated in vacuo. The residue was purified by silica flashchromatography (DCM/methanol 4:1) to provide the title compound (200 mg,64% yield) as a brown solid. LCMS (ESI): [M+H]⁺=156.1.

Step 9:(S)—N-(6-Fluoro-2,3-dimethyl-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylmethanesulfonamide

The title compound was prepared according to Example 27 to provide thetitle compound (27.3 mg, 15.6% yield) as a white solid.

Example 401-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(Compound 176)

Step 1: Benzyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of 2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine(500 mg, 2.39 mmol), benzyl(3S,5S)-3-amino-5-fluoro-piperidine-1-carboxylate (481 mg, 1.91 mmol),cesium fluoride (1088 mg, 7.16 mmol), N,N-diisopropylethylamine (1.38mL, 8.35 mmol) in DMSO (10 ml) was stirred at 80° C. for 3 h. Themixture was diluted with brine and extracted with ethyl acetate followedby concentration of the extracts under vacuum. The residue was purifiedby silica flash chromatography (petroleum ether/ethyl acetate 1:1) toafford the title compound (526 mg, 51.8% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=426.1.

Step 2: Benzyl(3S,5S)-3-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate

Under nitrogen, a solution of benzyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(150 mg, 0.35 mmol), 4-amino-2,3,5-trifluoro-phenol (86.3 mg, 0.53mmol), cesium carb<Miate (574 mg, 1.76 mmol) in DMSO (10 mL) was stirredfor 2 h at 100° C. The reaction was quenched with brine and extractedwith ethyl acetate. The organic extract was concentrated in vacuo. Theresidue was purified by silica flash chromatography (petroleumether/ethyl acetate 1:1) to afford the title compound (190 mg, 62.6%yield). LCMS (ESI): (M+Na)⁺=591.2.

Step 3:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide

Under nitrogen, a solution of benzyl(3S,5S)-3-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate(289 mg, 0.33 mmol), alpha-toluenesulfonylchloride (89 mg, 0.47 mmol),pyridine (0.54 mL, 6.68 mmol) in DCM (2 mL) was stirred for 2 h at roomtemperature. The reaction was quenched with water and extracted withethyl acetate followed by removal of the solvent under vacuum. Theresidue was purified by silica flash chromatography eluting withpetroleum ether/ethyl acetate (1/1) to afford the title compound (180mg, 74.5% yield) as a yellow solid.

A solution of benzyl(3S,5S)-3-((4-(2-(4-(benzylsulfonylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate(150 mg, 0.21 mmol) in DCM (4 mL) and 33% HBr in acetic acid (1 mL) wasstirred for 2 h at 25° C. The solvent was removed under vacuum. Theresidue was purified by prep-HPLC to provide the title compound (43.0mg, 35.2% yield) as a white solid.

Example 41N-(4-((3-(2-(3-Azabicyclo[3.1.0]hexan-5-ylamino)pyrimidin-4-yl)-2-pyridyl)oxy)-2,3-difluoro-phenyl)-1-phenyl-methanesulfonamide&N-(4-((3-(2-(3-azabicyclo[3.1.0]hexan-5-ylamino)pyrimidin-4-yl)-2-pyridyl)oxy)-2,3-difluoro-phenyl)-1-phenyl-methanesulfonamide(Compound 185 & Compound 186)

The title compound was prepared according to Example 38. The residue wassubjected to chiral HPLC to provide two single stereoisomers.

Isomer 1 (Compound 185):N-(4-((3-(2-(3-Azabicyclo[3.1.0]hexan-5-ylamino)pyrimidin-4-yl)-2-pyridyl)oxy)-2,3-difluoro-phenyl)-1-phenyl-methanesulfonamide(14.4 mg, 9.4% yield), obtained as a white solid, (rt=7.396 min,Chiralpak Cellulose-SB, 0.46×15 cm; 5 μm, Hex(0.1% IPA):EtOH=70:30, 1.0mL/min).

Isomer 2 (Compound 186):N-(4-((3-(2-(3-Azabicyclo[3.1.0]hexan-5-ylamino)pyrimidin-4-yl)-2-pyridyl)oxy)-2,3-difluoro-phenyl)-1-phenyl-methanesulfonamide(9.1 mg, 6% yield), obtained as a white solid, (rt=8.935 min, ChiralpakCellulose-SB, 0.46×15 cm; 5 μm, Hex(0.1% IPA):EtOH=70:30, 1.0 mL/min).

Example 421-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(Compound 190)

Step 1: 1-(tert-Butyl) 2-methyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl)-2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (20.0 g, 81.54 mmol) andimidazole (16.7 g, 244.6 mmol) in DMF (100 mL) was addedtert-butyldiphenylchlorosilane (31.81 mL, 122.3 mmol) dropwise at 0° C.The resulting solution was allowed to react for 16 h at roomtemperature. The reaction was quenched with water and then extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography(petroleum ether/ethyl acetate 10:1) to afford the title compound (39 g,98.9% yield) as a white solid. LCMS (ESI):

-   -   [M+H]⁺=484.1.

Step 2: 1-(tert-butyl) 2-methyl(2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylateand 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate

Under nitrogen, to a solution of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (35.0 mL, 289.5 mmol)in THF (200 mL) was added lithium diisopropylamide (41.4 mL, 82.7 mmol,2 M THF solution) dropwise at −20° C., and the solution was stirred formin at the same temperature. A solution of 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate(20.0 g, 41.4 mmol) in THF (100 mL) was added to the above solutiondropwise at −20° C. The resulting solution was stirred for 1 h at 0° C.The solution was cooled to −78° C., and iodomethane (19.3 mL, 310.1mmol) was added dropwise. The reaction mixture was allowed to stir for 4h at room temperature. The reaction was then quenched with saturatedaqueous ammonium chloride solution. The resulting solution was extractedwith ethyl acetate, and the organic layer was washed with brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by silica flash chromatographyeluting with petroleum ether/ethyl acetate (5/1) and the twodiastereoisomers were separated. 1-(tert-butyl) 2-methyl(2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate(5.5 g, 27% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=498.2; ¹H NMR(300 MHz, CDCl₃) δ 7.68-7.60 (m, 4H), 7.44-7.39 (m, 6H), 4.35-4.27 (m,1H), 3.73 (d, J=4.2 Hz, 3H), 3.68-3.59 (m, 1H), 3.51-3.42 (m, 1H),2.34-2.25 (m, 1H), 1.99-1.83 (m, 1H), 1.43-1.34 (m, 12H), 1.06 (d, J=7.7Hz, 9H). The other isomer (1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate)was obtained as a yellow oil (12.5 g, 61% yield). LCMS (ESI):[M+H]⁺=498.2; ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.58 (m, 4H), 7.46-7.32 (m,6H), 4.41-4.28 (m, 1H), 3.67-3.34 (m, 5H), 2.21-2.08 (m, 1H), 2.04 (s,2H), 1.99-1.86 (m, 1H), 1.41 (d, J=4.7 Hz, 8H), 1.06 (s, 9H).

Step 3: Methyl(2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-2-carboxylate

To a solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate(15.0 g, 30.1 mmol) in DCM (100 mL) was added TFA (10 mL). The mixturewas stirred for 16 h at room temperature, and the solvent was thenremoved under vacuum. The crude product was used in the next stepwithout further purification. LCMS (ESI): [M+H]⁺=398.2.

Step 4: Methyl(2R,4R)-1-benzyl-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-2-carboxylate

To a solution of methyl(2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-2-carboxylate(11.98 g, 30.14 mmol) in acetonitrile (40 mL) was added potassiumcarbonate (12.86 g, 93.03 mmol) at room temperature. Benzyl bromide(4.32 mL, 36.33 mmol) was then added dropwise, and the mixture wasstirred for 16 h at room temperature. The solids were filtered off andthe filtrate was concentrated in vacuo and purified by silica flashchromatography (ethyl acetate/petroleum ether 0-20%) to afford the titlecompound (13.4 g, 91.2% yield) as a light yellow oil. LCMS (ESI):[M+H]⁺=488.1.

Step 5: Methyl(2R,4R)-1-benzyl-4-hydroxy-2-methylpyrrolidine-2-carboxylate

To a solution of methyl(2R,4R)-1-benzyl-4-((tert-butyldiphenylsilyl)oxy)-2-methylpyrrolidine-2-carboxylate(13.4 g, 27.5 mmol) in THF (30 mL) was added 1 M tetrabutylammoniumfluoride in THF (31.4 mL, 31.4 mmol) at room temperature. The reactionmixture was stirred for 4 h at room temperature. The reaction mixturewas quenched with brine and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue was purified by silicaflash chromatography (petroleum ether/ethyl acetate 1:1) to afford thetitle compound (6.6 g, 92.9% yield) as a yellow oil. LCMS (ESI):[M+1]⁺=250.2.

Step 6: Methyl(2R,4R)-1-benzyl-2-methyl-4-((methylsulfonyl)oxy)pyrrolidine-2-carboxylate

To a solution of methyl(2R,4R)-1-benzyl-4-hydroxy-2-methyl-pyrrolidine-2-carboxylate (12.0 g,48.1 mmol) in DCM (50 mL) was successively added triethylamine (20.0 mL,144 mmol) and methanesulfonyl chloride (4.22 mL, 54.5 mmol) at 0° C. Themixture was stirred for 1 h at room temperature and then quenched withwater followed by extraction with DCM. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by silica flash chromatography (ethylacetate/petroleum ether 0-40%) to afford the title compound (14.2 g,90.1% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=328.2.

Step 7: Methyl(2R,4S)-4-azido-1-benzyl-2-methylpyrrolidine-2-carboxylate

To a solution of methyl(2R,4R)-1-benzyl-2-methyl-4-((methylsulfonyl)oxy)pyrrolidine-2-carboxylate(14.2 g, 43.4 mmol) in DMF (50 mL) was added sodium azide (3.7 g, 56.9mmol) at room temperature followed by stirring at 70° C. for 4 h. Thereaction was quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified bysilica flash chromatography (ethyl acetate/petroleum ether 0-20%) toafford the title compound (10.3 g, 86.6% yield) as a yellow oil. LCMS(ESI): [M+H]⁺=275.1.

Step 8: ((2R,4S)-4-Amino-1-benzyl-2-methylpyrrolidin-2-yl)methanol

To a solution of methyl(2R,4S)-4-azido-1-benzyl-2-methyl-pyrrolidine-2-carboxylate (10.3 g,37.6 mmol) in THF (100 mL) was added lithium aluminium hydride (3.0 g,79.0 mmol) at 0° C. The reaction mixture was stirred for 4 h at roomtemperature and was then quenched with water (3 mL), 15% sodiumhydroxide solution (3 mL) and water (9 mL). The solids were filtered.The filtrate was concentrated in vacuo to afford the title compound as ayellow oil thatwas used in the next step without further purification.LCMS (ESI): [M+H]⁺=221.0.

Step 9: tert-Butyl((3S,5R)-1-benzyl-5-(hydroxymethyl)-5-methylpyrrolidin-3-yl)carbamate

A solution of di-tert-butyldicarbonate (9.83 g, 45.1 mmol) and ((2ft,4S)-4-amino-1-benzyl-2-methylpyrrolidin-2-yl)methanol (8.27 g, 37.6mmol) in THF (40 mL) was stirred for 4 h at 25° C. The solvent wasremoved in vacuo and the residue purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (0-30%) to afford the titlecompound (11.8 g, 98.1% yield) as a yellow oil. LCMS (ESI):[M+H]⁺=321.0.

Step 10: tert-Butyl((3S,5S)-1-benzyl-5-fluoro-5-methylpiperidin-3-yl)carbamate

To a solution of tert-butyl((3S′,5R)-1-benzyl-5-(hydroxymethyl)-5-methylpyrrolidin-3-yl)carbamate(6.0 g, 18.7 mmol) in DCM (50 mL) was added diethylaminosulfurtrifluoride (3.7 mL, 28.1 mmol) at 0° C. The mixture was stirred for 4 hat room temperature. The reaction was quenched with saturated aqueoussodium carbonate solution and extracted with DCM. The solvent wasremoved under vacuum, and the residue was purified by silica flashchromatography (ethyl acetate/petroleum ether 0-20%) to afford the titlecompound (5.8 g, 96.1% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=323.2.

Step 11: tert-Butyl N-((3S,5S)-5-fluoro-5-methyl-3-piperidyl)carbamate

A mixture of tert-butylN-((3S,5S)-1-benzyl-5-fluoro-5-methyl-3-piperidyl)carbamate (5.7 g, 17.7mmol) and 10% Pd/C (2.0 g, 1.9 mmol) in methyl alcohol (40 mL) underhydrogen atmosphere was stirred for 2 h at 25° C. The mixture wasfiltered, and the filtrate was concentrated in vacuo to afford the crudeproduct which was used in the next step without further purification.LCMS (ESI): [M+H]⁺=233.3.

Step 12: Benzyl(3S,5S)-5-(tert-butoxycarbonylamino)-3-fluoro-3-methyl-piperidine-1-carboxylate

To a solution of tert-butylN-((3S,5S)-5-fluoro-5-methyl-3-piperidyl)carbamate (4.4 g, 17.7 mmol)and N,N-diisopropylethylamine (8.76 mL, 53.0 mmol) in DCM (35 mL) wasadded benzyl chloroformate (2.74 mL, 19.4 mmol) at 0° C. The reactionmixture was stirred for 2 h at 25° C. The reaction mixture wasconcentrated in vacuo, and the residue was purified by silica flashchromatography (ethyl acetate/petroleum ether 0-20%) to afford the titlecompound (5.1 g, 78.7% yield) as a light yellow solid. LCMS (ESI):[M+H]⁺=367.2; ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.30 (m, 5H), 5.29-5.07 (m,2H), 4.52-4.14 (m, 2H), 3.83 (s, 1H), 2.94-2.12 (m, 3H), 1.67-1.38 (m,12H).

Step 13: Benzyl(3S,5S)-5-amino-3-fluoro-3-methyl-piperidine-1-carboxylate

To a solution of benzyl(3S,5S)-5-tert-butoxycarbonylamino)-3-fluoro-3-methyl-piperidine-1-carboxylate(200 mg, 0.55 mmol) in DCM (6 mL) was added a solution of 4 M HCl in1,4-dioxane (1.5 mL, 6 mmol). The reaction mixture was stirred for 1 hat 25° C. The solvent was removed under vacuum to afford the titlecompound which was used in the next step without purification. LCMS(ESI): [M+H]⁺=267.0.

Step 14: Benzyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)-3-methy1-piperidine-1-carboxylate

Under nitrogen, to a solution of((3S,5S)-1-benzyloxycarbonyl-5-fluoro-5-methyl-3-piperidyl)ammoniumchloride (0.58 g, 2.17 mmol), 2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine(0.77 g, 3.68 mmol) and cesium fluoride (0.99 g, 6.5 mmol) in DMSO (7mL) was added N,N-diisopropylethylamine (0.84 g, 6.5 mmol) at 20° C. Theresulting solution was stirred for 7.5 h at 80° C. The reaction mixturewas quenched with water and extracted with ethyl acetate. The organicextract was washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica flashchromatography (ethyl acetate/petroleum ether 1:1) to afford the titlecompound (400 mg, 42% yield) as a yellow solid. LCMS (ESI):[M+H]⁺=440.5.

Step 15: Benzyl(3S,5S)-5-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-3-fluoro-3-methyl-piperidine-1-carboxylate

Under nitrogen, a mixture of benzyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)-3-methyl-piperidine-1-carboxylate(0.38 g, 0.86 mmol), 4-amino-2,3,5-trifluoro-phenol (0.16 g, 0.95 mmol)and cesium carbonate (0.56 g, 1.73 mmol) in DMSO (4 mL) was stirred for2 h at 100° C. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic extract was washed with brine and driedover anhydrous sodium sulfate, followed by concentration under vacuum.The residue was purified by silica flash chromatography (ethylacetate/petroleum ether 1:1) to afford the title compound (300 mg, 59.6%yield) as a brown solid. LCMS (ESI): [M+H]⁺=583.2.

Step 16: Benzyl(3S,5S)-5-((4-(2-(4-(benzylsulfonylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-3-fluoro-3-methyl-piperidine-1-carboxylate

To a solution of benzyl(3S,5S)-5-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-3-fluoro-3-methyl-piperidine-1-carboxylate(0.15 g, 0.26 mmol) in pyridine (1.5 mL) was addedalpha-toluenesulfonylchloride (0.07 g, 0.39 mmol) at 20° C. Theresulting solution was stirred for 2 h at 20° C. The reaction mixturewas diluted with water and extracted with ethyl acetate. The organicextract was washed with brine and dried over anhydrous sodium sulfate,followed by concentration under vacuum. The residue was purified bysilica flash chromatography (ethyl acetate/petroleum ether 4:1) toafford the title compound (150 mg, 79.1% yield) as a brown solid. LCMS(ESI): [M+H]⁺=737.2.

Step 17:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methyl-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide

To a solution of benzyl(3S,5S)-5-((4-(2-(4-(benzylsulfonylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-3-fluoro-3-methyl-piperidine-1-carboxylate(150 mg, 0.20 mmol) in DCM (2 mL) was added 33% HBr in acetic acid (2.0mL). The reaction mixture was stirred at 20° C. for 30 min and thesolvent was concentrated under vacuum. The residue was purified byprep-HPLC to afford the title compound (33.3 mg, 17.7% yield) as a whitesolid.

Example 43(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)benzyl)cyclopropanecarboxamide(Compound 197)

Step 1: Benzyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a mixture of benzyl (3S)-3-aminopiperidine-1-carboxylate (1.28 g,5.46 mmol) in DMSO (12 mL) was added2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine (1.63 g, 7.78 mmol), cesiumfluoride (1.58 g, 10.4 mmol) and N,N-diisopropylethylamine (2.9 mL,16.38 mmol). The reaction mixture was stirred at 80° C. for 2 h and wasthen diluted with water. The mixture was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicaflash chromatography (ethyl acetate/petroleum ether 10-40%) to affordthe title compound (1.8 g, 80.9% yield) as a yellow solid. LCMS (ESI):[M+H]⁺=408.1.

Step 2: Benzyl(3S)-3-((4-(2-(3-bromo-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a mixture of benzyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(1.1 g, 2.7 mmol) and 3-bromo-2-fluoro-phenol (0.66 g, 3.46 mmol) inDMSO (20 mL) was added cesium carbonate (1.75 g, 5.37 mmol). The mixturewas stirred for 1 h at 110° C. The mixture was diluted with water andextracted with ethyl acetate, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica flashchromatography (ethyl acetate/petroleum ether, 10-40%) to afford thetitle compound (1.2 g, 76.8% yield) as a light yellow solid. LCMS (ESI):[M+H]⁺=578.3.

Step 3: Benzyl(3S)-3-((4-(2-(3-((tert-butoxycarbonylamino)methyl)-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a mixture of benzyl(3S)-3-((4-(2-(3-bromo-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(0.76 g, 1.31 mmol), potassium(((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.12 g, 4.7 mmol),cesium carbonate (1.32 g, 4.05 mmol) in 1,4-dioxane (18 mL) and water (3mL) was added palladium(II)acetate (0.08 g, 0.34 mmol) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.21 g, 0.51 mmol). Themixture was stirred for 16 h at 110° C., diluted with water andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate and concentrated under vacuum. The residue waspurified by silica flash chromatography (ethyl acetate/petroleum ether20-70%) to afford the title product (550 mg, 66.6% yield) as a lightyellow solid. LCMS (ESI): [M+H]⁺=629.3.

Step 4: Benzyl(3S)-3-((4-(2-(3-((cyclopropanecarbonylamino)methyl)-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of benzyl(3S)-3-((4-(2-(3-((tert-butoxycarbonylamino)methyl)-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(0.26 g, 0.41 mmol) in DCM (3 mL) was added 4 M HCl in 1,4-dioxane (9mL). The reaction mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated in vacuo and used in the next step without purification.The residue was dissolved in pyridine (1.5 mL), and cyclopropanecarbonylchloride (68 mg, 0.66 mmol) was added at 20° C. The resulting solutionwas stirred for 1 h at 20° C. The reaction mixture was diluted withwater and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by silica flash chromatography (ethylacetate/petroleum ether 70:30) to afford the title compound (190 mg,96.2% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=597.3.

Step 5:(S)—N-(2-Fluoro-3-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)benzyl)cyclopropanecarboxamide

A solution of benzyl(3S)-3-((4-(2-(3-((cyclopropanecarbonylamino)methyl)-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(0.15 g, 0.25 mmol) in DCM (2 mL) was stirred at 20° C. 33% HBr inacetic acid (1 mL) was then added and the reaction mixture was stirredat 20° C. for 1 h. The solvent was removed in vacuo and the residue waspurified by prep-HPLC to provide the title compound (24.4 mg, 20.8%yield) as a white solid.

Example 441-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 1) &1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 2) (Compound 198 & Compound 199)

Step 1: tert-Butyl3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 3-methylenepiperidine-1-carboxylate (500 mg,2.53 mmol) in DMF (10 mL) was added 9-borabicyclo(3.3.1)nonane (310 mg,2.54 mmol) at 0° C. The resulting solution was stirred for 1 h at 75° C.Then 2-chloro-4-(2-fluoro-3-pyridyl)pyrimidine (550 mg, 2.62 mmol),potassium carbonate (1.05 g, 7.6 mmol),(1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (185 mg, 0.25mmol), and water (2 mL) were added. The mixture was stirred at 75° C.for 1.5 h under nitrogen. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic extract was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica flash chromatography (ethyl acetate/petroleum ether3:7) to afford the title compound (550 mg, 55.4% yield) as a whitesolid. LCMS (ESI): [M+H]⁺=373.2.

Step 2: tert-Butyl3-((4-(2-(4-amino-2,3,5-trifluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)methyl)piperidine-1-carboxylate

Under nitrogen, a mixture of tert-butyl3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)methyl)piperidine-1-carboxylate(258 mg, 0.69 mmol), 4-amino-2,3,5-trifluoro-phenol (100 mg, 0.61 mmol)and cesium carbonate (400 mg, 1.23 mmol) in DMSO (5 mL) was stirred for2 h at 100° C. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic extract was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography using ethyl acetate/petroleum ether (2/3) toafford the title compound (220 mg, 48.7% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=516.2

Step 3: tert-Butyl3-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl3-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)methyl)piperidine-1-carboxlate(180 mg, 0.35 mmol) and pyridine (200 mg, 2.53 mmol) in DCM (1.5 mL) wasadded alpha-toluenesulfonylchloride (110 mg, 0.58 mmol) followed bystirring at 25° C. for 2 h. The reaction mixture was diluted with waterand the resulting solution was extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica flashchromatography (ethyl acetate/petroleum ether 45:55) to afford the titlecompound (190 mg, 40.6% yield) as a yellow solid. LCMS (ESI):[M+H]⁺=670.2.

Step 4:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 1) &1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(piperidin-3-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 2)

To a solution of tert-butyl3-((4-(2-(4-(benzylsulfonylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)methyl)piperidine-1-carboxylate(190 mg, 0.28 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (4mL, 16 mmol). The reaction mixture was stirred at 25° C. for 1 h and thesolvent then removed under vacuum. The crude product was purified byprep-HPLC to separate the two enantiomers.

Isomer 1 (Compound 198):1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(3-piperidylmethyl)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(7.4 mg, 4.5% yield), obtained as a white solid, (rt=3.649 min, IC,0.46×10 cm; 5 μm, MTBE(0.2% isopropylamine):EtOH=70:30, 1.0 mL/min).

Isomer 2 (Compound 199):1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(3-piperidylmethyl)pyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(11.4 mg, 7% yield), obtained as a white solid, (rt=5.095 min, IC,0.46×10 cm; 5 μm, MTBE (0.2% isopropylamine):EtOH=70:30, 1.0 mL/min).

Example 451,1,1-Trifluoro-3-((2-fluoro-3-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol&1,1,1-trifluoro-3-((2-fluoro-3-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol(Compound 200 & Compound 201)

Step 1: tert-Butyl(3S)-3-((4-(2-(2-fluoro-3-((3,3,3-trifluoro-2-hydroxypropyl)amino)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-((4-(2-(3-amino-2-fluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(100 mg, 0.21 mmol) and calcium trifluoromethanesulfonate (70 mg, 0.21mmol) in acetonitrile (5 mL) was added 1,1,1-trifluoro-2,3-epoxypropane(0.094 g, 0.8400 mmol) at 25° C. The resulting solution was stirred for48 h at 60° C. The reaction was quenched with water. The resultingsolution was extracted with ethyl acetate and the organic layers werecombined. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica flashchromatography (ethyl acetate/petroleum ether 4:6) to provide the titlecompound (30 mg, 14.6% yield) as a yellow solid. LCMS (ESI):[M+H]⁺=593.4.

Step 2:1,1,1-Trifluoro-3-((2-fluoro-3-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol(isomer 1) &1,1,1-trifluoro-3-((2-fluoro-3-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol(isomer 2)

To a solution of tert-butyl(3S)-3-((4-(2-(2-fluoro-3-((3,3,3-trifluoro-2-hydroxy-propyl)amino)phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.080 mmol) in DCM (1 mL) was added 4 M HCl in 1,4-dioxane (1mL). The resulting solution was stirred for 1 h at 25° C. and thesolvent removed under vacuum. The residue was purified by prep-HPLC andthe two single diastereomers separated via chiral-HPLC.

Isomer 1 (Compound 200):1,1,1-Trifluoro-3-(2-fluoro-3-((3-(2-(((3S)-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)anilino)propan-2-ol(16.4 mg, 39.3% yield), obtained as a light yellow solid, (rt=3.602 min,ADH, 0.46×10 cm; 5 μm, Hex(0.1% DEA), EtOH=70:30, 1.0 mL/min).

Isomer 2 (Compound 201):1,1,1-Trifluoro-3-(2-fluoro-3-((3-(2-(((3S)-3-piperidyl)amino)pyrimidin-4-yl)-2-pyridyl)oxy)anilino)propan-2-ol(isomer 2) (17.1 mg, 40.9% yield), obtained as a light yellow solid,(rt=4.704 min, ADH, 0.46×10 cm; 5 μm, Hex (0.1% DEA):EtOH=70:30, 1.0mL/min).

Example 46N-[2,3-Difluoro-4-[[3-[2-[[(3S)-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]-3,5-difluoro-benzenesulfonamide(Compound 206) Step 1: tert-Butyl(3S)-3-[[4-[2-[4-[(3,5-difluorophenyl)sulfonylamino]-2,3-difluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

To a two-dram pressure-cap relief vial was added tert-butyl(S)-3-((4-(2-(4-amino-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(50 mg, 0.10 mmol) dissolved in DCM (0.5 mL), pyridine (0.12 mL), and3,5-difluorobenzenesulfonyl chloride (32 mg, 0.15 mmol). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas then washed with HCl (1N, 2 mL), concentrated, and transitioned toStep 2. LCMS (ESI): [M+H]⁺=675.4.

Step 2:(S)—N-(2,3-Difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3,5-difluorobenzenesulfonamide

To a solution of tert-butyl(3S)-3-[[4-[2-[4-[(3,5-difluorophenyl)sulfonylamino]-2,3-difluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(crude residue) in methanol (1.4 mL) was added hydrochloric acid (4 N indioxane, 0.25 mL, 1.0 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The solution was concentrated in vacuo, dissolvedin dimethylformamide (1 mL) and purified by prep-HPLC to afford thetitle compound (3.8 mg, 6.7% yield). LCMS (ESI): [M+H]⁺=575.1.

Example 47N-[2-Fluoro-3-methyl-4-[[3-[2-[[(3S)-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]-1phenylmethanesulfonamide (Compound 237) Step 1:4-Amino-3-fluoro-2-methylphenol

To a solution of 3-fluoro-2-methyl-4-nitrophenol (860 mg, 5.02 mmol) inethanol (20 mL) was added palladium on carbon (10 mass %, 535 mg, 0.50mmol) and ammonium formate (2.50 g, 40.2 mmol), and the reaction washeated to 60° C. After ˜15 minutes (excessive hydrogen gas evolutionseen), the reaction mixture was cooled to room temperature, filteredthrough celite and concentrated to dryness. The crude intermediate wasre-suspended in DCM (20 mL) and treated with Biotage MP-TsOH resin (2.9g, 10.05 mmol) and then placed on an orbital shaker. After shakingovernight (18 h), the resin was collected, rinsed several times withDCM, and the title compound was obtained by rinsing the resin with 7Nammonia in methanol solution (2×10 mL) and subsequent evaporation undervacuum (148 mg, 21% yield). LCMS (ESI): [M+H]⁺=142.

Step 2: tert-Butyl(3S)-3-[[4-[2-(4-amino-3-fluoro-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

To a vial kept under nitrogen, tert-butyl(3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate(310 mg, 0.83 mmol) and 4-amino-3-fluoro-2-methylphenol (141 mg 0.10mmol) were added, followed by DMSO (3.3 mL, 47 mmol) and cesiumcarbonate (811 mg, 2.49 mmol). The vial was capped and heated to 130° C.for 16 h. Upon cooling, the crude intermediate was obtained throughtrituration from the reaction mixture via addition of water andsubsequent filtration. The material was then solubilized in DCM andextracted with brine. The organic layer was dried with magnesiumsulfate, filtered and concentrated in vacuo followed by silica columnchromatography to afford 260 mg (63.3% yield) of the title compound.LCMS (ESI): [M+l]⁺=495.

Step 3: tert-Butyl(3S)-3-[[4-[2-[4-(benzylsulfonylamino)-3-fluoro-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2yl]amino]piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-[[4-[2-(4-amino-3-fluoro-2-methyl-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylatein DCM (1 mL) was added pyridine (0.3 mL, 3.7 mmol) followed byalpha-toluenesulfonyl chloride (100 mg, 0.52 mmol). The reaction mixturewas stirred at room temperature for 16 h, quenched with 10 mL ofsaturated aqueous bicarbonate solution, and DCM was added. The organicextract was dried with anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The crude reaction mixture was purified bysilica column chromatography to afford 160 mg (94% yield) of the titlecompound. LCMS (ESI): [M+1]⁺=649.

Step 4:N-[2-Fluoro-3-methyl-4-[[3-[2-[[(3S)-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]-1phenylmethanesulfonamide

To a solution of tert-butyl(3S)-3-[[4-[2-[4-(benzylsulfonylamino)-3-fluoro-2-methyl-phenoxy]-3-pyridyl]pyrimidin-2yl]amino]piperidine-1-carboxylatein DCM (5 mL) was added 4M HCl in 1,4 dioxane (1.2 mL), and the reactionmixturewas stirred at room temperature for 4 h. Concentration to drynessunder vacuum and purification by prep-HPLC afforded 42.6 mg (30.5%yield) of the title compound. LCMS (ESI): [M+l]+=549.1.

Example 481-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-oneCompound 248 & Compound 249

Step 1: 1-(Benzyloxy)-4-bromo-2,3-difluorobenzene

Under nitrogen, a solution of 4-bromo-2,3-difluorophenol (2.0 g, 9.57mmol) and benzyl bromide (2.46 g, 14.35 mmol) in N,N-dimethylformamide(20 mL) was added potassium carbonate (3.% g, 28.71 mmol), the resultingsolution was stirred for 4 h at 25° C. The resulting solution wasdiluted with water, extracted with ethyl acetate, washed with brine,dried over sodium sulfate and concentrated. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(20:80) to afford the title compound (2.74 g, 90.9% yield) as a whitesolid. LCMS (ESI): [M+H]⁺=299.0.

Step 2: 1-(4-(Benzyloxy)-2,3-difluorophenyl)-3-ethylpyrrolidin-2-one

Under nitrogen, a solution of 1-benzyloxy-4-bromo-2,3-difluoro-benzene(300 mg, 1.00 mmol) and 3-ethylpyrrolidin-2-one (113 mg, 1.00 mmol) andpotassium carbonate (415 mg, 3.01 mmol),N¹,N²-dimethylethane-1,2-diamine (18 mL, 0.20 mmol) and copper(I) iodide(19 mg, 0.10 mmol) in 1,4-dioxane (5 mL) was stirred for 4 h at 110° C.The resulting solution was diluted with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica flash chromatography eluting withethyl acetate/petroleum ether (1/4) to afford the title compound (170mg, 48.6% yield) as a brown solid. LCMS (ESI): [M+H]⁺=332.1

Step 3: 1-(2,3-Difluoro-4-hydroxyphenyl)-3-ethylpyrrolidin-2-one

A solution of1-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-pyrrolidin-2-one (170 mg,0.51 mmol) and 10% Pd/C (50 mg) in methyl alcohol (3 mL) was stirred for2 h at rt under hydrogen. The solids were filtered out. Afterfiltration, the filtrate was concentrated under reduced pressure toafford the title compound (120 mg, 82.4% yield) as a brown solid. LCMS(ESI): [M+H]⁺=242.1.

Step 4: tert-Butyl(3S)-3-((4-(2-(4-(3-ethyl-2-oxopyrrolidin-1-yl)-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a mixture of1-(2,3-difluoro-4-hydroxy-phenyl)-3-ethyl-pyrrolidin-2-one (120 mg, 0.50mmol), tert-butyl (3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (222 mg, 0.60 mmol) and cesium carbonate (490mg, 1.49 mmol) in dimethyl sulfoxide (3 ml) was stirred for 4 h at 120°C. The resulting solution was diluted with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica flash chromatography eluting withethyl acetate/petroleum ether (60:40) to afford the title compound (250mg, 76.1% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=595.3

Step 5:1-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-one&1-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-oneCompound 248 & Compound 249

To a solution of tert-butyl(3S)-3-((4-(2-(4-(3-ethyl-2-oxo-pyrrolidin-1-yl)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(250 mg, 0.42 mmol) in dichloromethane (2 mL) was added 4 M HCl indioxane (5 mL), die mixture was stirred for 4 h at rt. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-HPLC and Chiral HPLC to afford the tide compound. After ChiralHPLC, two peaks were isolated out. The fast peak was assigned isomer 1.The slow peak was assigned isomer 2.

1-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-one(isomer 1) (29.7 mg, 7.1% yield) as a white solid, (rt=4.577 min,CHIRALPAKIC-3, 0.46*5 cm, 3 um, Hex(10 mmolNH₃):EtOH=50:50, 1.0 ml/min).

1-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-ethylpyrrolidin-2-one(isomer 2) (32 mg, 7.6% yield) as a white solid, (rt=5.709 min,CHIRALPAK IC-3, 0.46*5 cm, 3 um, Hex(10 mmolNH₃):EtOH=50:50, 1.0ml/min).

Example 49(S)-1-(4-Cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 250

The title compound was prepared according to example 27. This providesthe title compound (30.6 mg, 13.6%) as a white solid.

Example 501-(3,3-Difluorocyclobutyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 251

The title compound was prepared according to example 42. This resultedin the title compound (37.1 mg, 45.2% yield) as a white solid.

Example 512-Methoxy-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 252

The title compound was prepared according to example 40. This resultedin the title compound (3.0 mg, 15.1% yield) as a white solid.

Example 523,3-Difluoro-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)butane-1-sulfonamideCompound 253

The title compound was prepared according to example 40. This resultedin the title compound (34.6 mg, 40.1% yield) as a white solid.

Example 53N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(6-(trifluoromethyl)pyridin-3-yl)methanesulfonamideCompound 254

The title compound was prepared according to example 40. This providesthe title compound (12.8 mg, 19.6% yield) as a white solid.

Example 541-(4-Cyanophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)methanesulfonamideCompound 255

Step 1: 1,3,4-Trifluoro-5-methoxy-2-nitrobenzene

To a solution of 2,3,4,6-tetrafluoronitrobenzene (1.53 g, 7.84 mmol) inmethyl alcohol (15 mL) was added sodium methanolate (450 mg, 8.33 mmol)slowly and stirred at rt for 16 h. The solvent was concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (8%) to afford the title compound(820 mg, 45.4% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 6.70(ddd, J=11.5, 6.4, 2.2 Hz, 1H), 4.00 (s, 3H).

Step 2: 2,3,6-Trifluoro-4-methoxyaniline

A solution of 1,3,4-trifluoro-5-methoxy-2-nitro-benzene (1.5 g, 6.88mmol), ammonium chloride (2.6 g, 48.61 mmol) and iron (2.0 g, 35.81mmol) in ethanol (30 mL) and water (18 mL) was stirred at 95° C. for 16h. The solids were filtered out. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (7%) to affordthe tide compound (880 mg, 72.2% yield) as an off-white solid. LCMS(ESI): [M+H]⁺=178.0

Step 3: tert-ButylN-tert-butoxycarbonyl-N-(2,3,6-trifluoro-4-methoxy-phenyl)carbamate

A mixture of 2,3,6-trifluoro-4-methoxyaniline (880 mg, 4.47 mmol),4-dimethylaminopyridine (120 mg, 0.98 mmol), di-tert-butyldicarbonate(4.0 g, 18.33 mmol) in tetrahydrofuran (18 mL) were stirred at 75° C.for 12 h. The resulting solution was diluted with water, extracted withethyl acetate, washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (1/4) to afford the titlecompound (1.7 g, 90.7% yield) as a white solid. ¹H NMR (300 MHz, CD₃OD)δ 6.58 (ddd, J=10.9, 7.0, 2.3 Hz, 1H), 3.92 (s, 3H), 1.46 (s, 18H).

Step 4: tert-ButylN-tert-butoxycarbonyl-N-(2,3,6-trifluoro-4-methoxy-5-methyl-phenyl)carbamate

Under nitrogen, to a solution of tert-butylN-tert-butoxycarbonyl-N-(2,3,6-trifluoro-4-methoxy-phenyl)carbamate (816mg, 2.16 mmol) in tetrahydrofuran (16 mL) was added 2 M lithiumdiisopropylamide in tetrahydrofuran (2.4 mL, 4.8 mmol) at −60° C. Theresulting solution was stirred for 2 h at −20° C. Then iodomethane (760mg, 5.35 mmol) was added at −60° C. and stirred at −20° C. for 1 h. Thereaction was quenched with sat. ammonium chloride. The resultingsolution was extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with ethyl acetate/petroleum ether (18%) toafford the title compound (500 mg, 59.1% yield) as a white solid. ¹H NMR(300 MHz, DMSO-d₆) δ 3.98 (d, J=1.9 Hz, 3H), 3.17-3.03 (m, 3H), 1.46 (s,18H).

Step 5: 4-Amino-2,3,5-trifluoro-6-methylphenol

A mixture of tert-butylN-tert-butoxycarbonyl-N-(2,3,6-trifluoro-4-methoxy-5-methyl-phenyl)carbamate(550 mg, 1.41 mmol) and 40% hydrobromic acid (7 mL) in water (3 mL) wasstirred at 100° C. for 24 h. The organic layer was concentrated undervacuum. The crude product would be directly used in the next stepwithout purification. LCMS (ESI): [M+H]⁺=178.0

Step 6:2,3,6-Trifluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)aniline

To a mixture of 4-amino-2,3,5-trifluoro-6-methyl-phenol (170 mg, 0.48mmol), 4-amino-2,3,5-trifluoro-6-methy 1-phenol (170 mg, 0.48 mmol) andcesium carbonate (500 mg, 1.53 mmol) in dimethyl sulfoxide (3 mL) wasstirred for 4 h at 100° C. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with ethyl acetate/petroleum ether (20%) toafford the title compound (130 mg, 62.2% yield) as an off-white solid.LCMS (ESI): [M+H]⁺=379.1

Step 7:1-(4-Cyanophenyl)-N-(2,3,6-trifluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a solution of2,3,6-trifluoro-5-methyl-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(110 mg, 0.26 mmol) in pyridine (0.50 mL) was added(4-cyanophenyl)methanesulfonyl chloride (88 mg, 0.41 mmol), the mixturewas stirred at rt for 1 h. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with ethyl acetate/petroleum ether (1:1) toafford the title compound (130 mg, 86.6% yield) as a white solid. LCMS(ESI): [M+H]⁺=558.1

Step 8:1-(4-Cyanophenyl)-N-(2,3,6-trifluoro-5-methyl-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a solution of1-(4-cyanophenyl)-N-(2,3,6-trifluoro-5-methyl-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(115 mg, 0.21 mmol) in dichloromethane (3 mL) was added3-chloroperoxybenzoic acid (80 mg, 0.44 mmol), the mixture was stirredfor 2 h at rt. The reaction was quenched with sat. sodium sulfite. Theresulting solution was diluted with water, extracted with ethyl acetate,washed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (80%) to afford the title compound (120 mg,94.7% yield) as an off-white solid. LCMS (ESI): [M+H]⁺=590.1

Step 9: Benzyl(3S,5S)-3-((4-(2-(4-(((4-cyanophenyl)methyl)sulfonamido)-2,3,5-trifluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate

Under nitrogen, a mixture of benzyl(3S,5S)-3-amino-5-fluoro-piperidine-1-carboxylate (50 mg, 0.20 mmol),N,N-Diisopropylethylamine (70 mg, 0.54 mmol),1-(4-cyanophenyl)-N-(2,3,6-trifluoro-5-methyl-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(180 mg, 0.18 mmol), caesium fluoride (85 mg, 0.56 mmol) in dimethylsulfoxide (3 mL) was stirred at 90° C. for 2 h. The resulting solutionwas diluted with water, extracted with ethyl acetate, washed with brine,dried over sodium sulfate and concentrated. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(15%) to afford the title compound (100 mg, 68.8% yield) as an off-whitesolid. LCMS (ESI): [M+H]⁺=762.2

Step 10:1-(4-Cyanophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)methanesulfonamideCompound 255

To a solution of benzyl(3S,5S)-3-((4-(2-(4-(((4-cyanophenyl)methyl)sulfonamido)-2,3,5-trifluoro-6-methylphenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate(95 mg, 0.12 mmol) in dichloromethane (1 mL) was added 33% hydrobromicacid in acetic acid (0.5 mL) and stirred at rt for 1 h. The solvent wasremoved under vacuum. The crude product was purified by Prep-HPLC toafford the title compound (22 mg, 27.2% yield) as a white solid.

Example 551-(Pyridin-3-yl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 256

The title compound was prepared according to example 40. This providesthe title compound (26.1 mg, 53.4% yield) as a white solid.

Example 561-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 257

Step 1: Benzyl(2S,5S)-2-methyl-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Into the solution of1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(96 mg, 0.17 mmol) in dimethyl sulfoxide (1.5 mL) was added benzyl(2S,5S)-5-amino-2-methyl-piperidine-1-carboxylate hydrochloride (74 mg,0.26 mmol), cesium fluoride (79 mg, 0.52 mmol) andN,N-Diisopropylethylamine (0.15 mL, 0.91 mmol). The mixture was stirredfor 2.5 h at 90° C. under nitrogen. The mixture was diluted with ethylacetate and washed with water. The solution was dried over sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(20-70%) to afford the title compound (80 mg, 63.8% yield) as a lightbrown solid. LCMS (ESI): [M+H]⁺=719.2

Step 2:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 257

Into the solution of benzyl(2S,5S)-2-methyl-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(80 mg, 0.11 mmol) in dichloromethane (3 mL) was added 33% HBr in aceticacid (3 mL). The mixture was stirred at rt for 0.5 h. The mixture wasconcentrated under vacuum. The residue was purified with Prep-HPLC toafford the title compound (27 mg, 41.5% yield) as a white solid.

Example 57N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)pyrrolidine-1-sulfonamideCompound 258

Step 1:N-(2,3,6-Trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)pyrrolidine-1-sulfonamide

To a solution of2,3,6-trifluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(0.16 g, 0.45 mmol) in pyridine (1.2 mL) was addedpyrrolidine-1-sulfonyl chloride (0.76 g, 4.47 mmol), the mixture wasstirred at 45° C. for 1 h. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with ethyl acetate/petroleum ether (1:1) toafford the title compound (120 mg, 47.4% yield) as a light brown solid.LCMS (ESI): [M+H]⁺=498.1.

Step 2:N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)pyrrolidine-1-sulfonamideCompound 258

The title compound was prepared according to example 54. This providesthe title compound (25.0 mg, 64.7% yield) as a white solid.

Example 581-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 259

The title compound was prepared according to Example 40. This resultedin the title compound (14.9 mg, 19.2% yield) as a yellow solid.

Example 592,2,2-Trifluoro-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamidehydrochloride Compound 260

The title compound was prepared according to example 40. This resultedin the title compound (12.4 mg, 18% yield) as a white solid and as HClsalt.

Example 601-(l-Fluorocyclopropyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 261

The title compound was prepared according to Example 40. This resultedin the title compound (37.7 mg, 23.3% yield) as a white solid.

Example 611-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 266

Step 1: tert-Butyl(3R,5S)-3-(fluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a mixture of1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(110 mg, 0.20 mmol), N,N-Diisopropylethylamine (50 mg, 0.39 mmol),tert-butyl (3S,5R)-3-amino-5-(fluoromethyl)piperidine-1-carboxylate (40mg, 0.17 mmol) and caesium fluoride (70 mg, 0.46 mmol) in dimethylsulfoxide (2 mL) was stirred at 90° C. for 2 h under nitrogen. Theresulting solution was diluted with water, extracted with ethyl acetate,washed with brine, dried over Sodium sulfate and concentrated. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (80%) to afford the title compound (95 mg, 40.8%yield) as an off-white solid. LCMS (ESI): [M+H]⁺=703.2

Step 2:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 266

To a solution of tert-Butyl(3S,5S)-3-(fluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(90 mg, 0.07 mmol) in dichloromethane (0.5 mL) was added 4 M HCl indioxane (1 mL) and stirred at rt for 1 h. The solvent was concentratedunder vacuum. The crude product was purified by Prep-HPLC to afford thetitle compound (21 mg, 51.3% yield) as a white solid.

Example 62N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)piperidine-1-sulfonamideCompound 263

The title compound was prepared according to example 57. This resultedin the title compound (17.8 mg, 30.7% yield) as a white solid.

Example 631-(2,2-Difluorocyclobutyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 264 & Compound 265

The title compound was prepared according to example 40. The residue waspurified by Prep-HPLC and Chiral HPLC to afford the title compound.After Chiral HPLC, two peaks were isolated out. The fast peak wasassigned isomer 1. The slow peak was assigned isomer 2.

1-(2,2-Difluorocyclobutyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 1, Compound 264) (15.2 mg, 17% yield) as a white solid,(rt=2.039 min (CHIRALPAKIG-3, 0.46*5 cm; 3.5 um, MtBE(0.2% IPAmine):MeOH=90:10, 1.0 ml/min).

1-(2,2-Difluorocyclobutyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 2, Compound 265) (13.5 mg, 12% yield) as a white solid,(rt=3.503 min (CHIRALPAK IG-3, 0.46*5 cm; 3.5 um, MtBE(0.2% IPAmine):MeOH=90:10, 1.0 ml/min)

Example 644-(2-(4-(Dimethylsulfamoylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)-2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidineCompound 266

Step 1: Benzyl(3S,5S)-3-((4-(2-(4-((N,N-dimethylsulfamoyl)amino)-2,3,5-trifluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate

Under nitrogen, a solution of benzyl(3S,5S)-3-((4-(2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate(0.12 g, 0.20 mmol) in pyridine (0.25 mL) was added4-dimethylaminopyridine (0.05 g, 0.2 mmol) and dimethylsulfamoylchloride (0.1 g, 0.50 mmol) at 20° C. The resulting solution was stirredfor 48 h at 80° C. The reaction was quenched with water and extractedwith ethyl acetate and the organic layers were combined. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (2/1) to afford the title compound(50 mg, 36% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=676.5.

Step 4:4-(2-(4-(Dimethylsulfamoylamino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)-2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidineCompound 266

A solution of benzyl(3S,5S)-3-((4-(2-(4-((N,N-dimethylsulfamoyl)amino)-2,3,5-trifluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate(0.05 g, 0.07 mmol) in acetonitrile (1 mL) and dichloromethane (1 mL)was added dimethyl sulfide (1 mL) and boron trifluoride etherate (1 mL)at 0° C. The resulting solution was stirred for 1 h at 0° C. Thereaction was quenched with sat. sodium carbonate and extracted withdichloromethane. The organic layers were combined. The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product was purified by Prep-HPLC to afford the title compound(15.2 mg, 42.1% yield) as a white solid.

Example 652-Cyclopropyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 267

The title compound was prepared according to example 40. This providesthe title compound (34.8 mg, 39.1% yield) as a white solid.

Example 662,2-Difluoro-N-(2,3,6-trifluoro-4-((5-fluoro-3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)butane-1-sulfonamideCompound 268

The title compound was prepared according to example 40. This providesthe title compound (20.0 mg, 38.4% yield) as a white solid.

Example 674-(2-(4-((Ethyl(methyl)sulfamoyl)amino)-2,3,5-trifluoro-phenoxy)-3-pyridyl)-2-(((3S,5S)-5-fluoro-3-piperidyl)amino)pyrimidineCompound 269

The title compound was prepared according to example 64. This providesthe title compound (17.0 mg, 42.2% yield) as a white solid.

Example 682,2-Difluoro-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)-6-methylpyridin-2-yl)oxy)phenyl)butane-1-sulfonamideCompound 270

The title compound was prepared according to example 40. This resultedin the title compound (3.5 mg, 5% yield) as an off-white solid.

Example 691-(2,2-Difluorocyclopropyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 271

The title compound was prepared according to example 40. This resultedin the title compound (90 mg, 92.1% yield) as a brown solid.

Example 70N-(4-((3-(2-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride Compound 272

The title compound was prepared according to example 38. This providesthe title compound (29 mg, 35.1% yield) as a light yellow solid and asHCl salt.

Example 71N-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamideCompound 273 & Compound 274

Step 1: N-(4-Bromo-2,3-difluorophenyl)-1-phenylmethanesulfonamide

Under nitrogen, to a solution of 4-bromo-2,3-difluoro-aniline (2.0 g,9.62 mmol) in toluene (20 mL) was added thionylchloride (1.5 mL, 20.68mmol) and stirred for 2 h at 90° C. The solvent was removed undervacuum. The residue was dissolved in dry tetrahydrofuran (20 mL) and 1 Mbenzylmagnesiumbromide in tetrahydrofuran (15 mL) was added at 0° C. Theresulting solution was stirred for 16 h at rt. The reaction was quenchedwith methanol. The resulting solution was diluted with water, extractedwith ethyl acetate, washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (1:1) to afford the titlecompound (2.5 g, 67.6% yield) as an off-white solid. LCMS (ESI):[M+H]⁺=347.0

Step 2:N-(Bromo-2,3-difluorophenyl)-N′-methyl-1-phenylmethanesulfonimidamide

Under nitrogen, a solution ofN-(4-bromo-2,3-difluoro-phenyl)-1-phenyl-methanesulfinamide (600 mg,1.73 mmol) in Carbon tetrachloride (12 mL) was added tert-butylhypochlorite (0.4 mL, 3.56 mmol) at 0° C. and stirred for 2 h at thesame temperature. Then 2 M methylamine in tetrahydrofuran (5 mL) wasadded into the mixture and stirred for 2 h at 0° C. The reaction wasquenched with brine and extracted with ethyl acetate. The solvent wasremoved under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (1/1) toafford the title compound (330 mg, 45.7% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=375.0.

Step 3:N-(2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N′-methy1-1-phenylmethanesulfonimidamide

Under nitrogen, a solution ofN-(4-bromo-2,3-difluorophenyl)-N′-methyl-1-phenylmethanesulfonimidamide(280 mg, 0.75 mmol), bis(pinacolato)diboron (380 mg, 1.50 mmol),Potassium Acetate (190 mg, 1.94 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (100 mg,0.13 mmol) in 1,4-dioxane (6 mL) was stirred for 2 h at 90° C. Thesolvent was removed under vacuum to afford the title compound (800 mg,76.2% yield) as a brown solid. The crude product would be directly usedin the next step without purification. LCMS (ESI): [M+H]⁺=423.2

Step 4:N-(2,3-Difluoro-4-hydroxyphenyl)-N′-methyl-1-phenylmethanesulfonimidamide

To a solution ofN-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N′-methyl-1-phenylmethanesulfonimidamide(800 mg, 0.57 mmol) in tetrahydrofuran (6 mL) was added sodium hydroxidein water (2 mL, 2M) and hydrogen peroxide (230 mg, 2.03 mmol), thenstirred at rt for 0.5 h. The reaction was quenched with sat. sodiumsulfite. The resulting solution was diluted with water, extracted withethyl acetate, washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica flash chromatographyeluting with dichloromethane/methanol (97:3) to afford the titlecompound (130 mg, 65.9% yield) as a brown solid. LCMS (ESI):[M+H]⁺=313.1.

Step 5: tert-Butyl(3S)-3-((4-(2-(2,3-difluoro-4-((N′-methyl-1-phenylmethyl)sulfonoamidimidamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture ofN-(2,3-difluoro-4-hydroxyphenyl)-N-methyl-1-phenylmethanesulfonimidamide(170 mg, 0.49 mmol), tert-butyl(3S)-3-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(250 mg, 0.67 mmol) and cesium carbonate (306 mg, 0.94 mmol) in dimethylsulfoxide (4 mL) was stirred at 80° C. for 1 h. The resulting solutionwas diluted with water, extracted with ethyl acetate, washed with brine,dried over sodium sulfate and concentrated. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(1/1) to afford the title compound (230 mg, 66.3% yield) as a brownsolid. LCMS (ESI): [M+H]⁺=666.3

Step 6:N-(2,3-Difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamide&N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamideCompound 273 & Compound 274

A solution of tert-butyl(3S)-3-((4-(2-(4-((S-benzyl-N-methyl-sulfonimidoyl)amino)-2,3-difluoro-phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(300 mg, 0.45 mmol) in dichloromethane (2 mL) was added 4 M HCl indioxane (1 mL) dropwise and stirred at rt for 1 h. The solvent wasconcentrated under vacuum. The residue was purified by Prep-HPLC andChiral HPLC to afford the title compound. After Chiral HPLC, two peakswere isolated out. The fast peak was assigned isomer 1. The slow peakwas assigned isomer 2.

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamide(isomer 1, Compound 273) (45.3 mg, 17.6% yield) as a white solid,(rt=5.122 min, CHIRALPAKIG-3, 0.46*5 cm, 3 um, MtBE(0.1%DEA):EtOH=70:30, 1.0 ml/min).

N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N′-methyl-1-phenylmethanesulfonimidamide(isomer 2, Compound 274) (31.0 mg, 12% yield) as a white solid,(rt=8.972 min, CHIRALPAK IG-3, 0.46*5 cm, 3 um, MtBE(0.1%DEA):EtOH=70:30, 1.0 ml/min).

Example 721-(2-Fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 275

The title compound was prepared according to example 42. This resultedin the title compound (19.5 mg, 50.5% yield) as a white solid.

Example 731-(4-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)ureaCompound 276

Step 1: Benzyl(3S,5S)-3-fluoro-5-((4-(2-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of benzyl(3S,5S)-3-((4-(2-(4-aminophenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate(70 mg, 0.14 mmol) in dichloromethane (2 mL) was added3-(trifluoromethyl)phenyl isocyanate (50 mg, 0.27 mmol) and stirred for1 h at rt. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layers were combined. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by silica flash chromatography eluting withethyl acetate/petroleum ether (1/2) to afford the title compound (47 mg,49.2% yield) as a brown solid. LCMS (ESI): [M+H]⁺=702.3.

Step 2:1-(4-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)ureaCompound 276

A solution of benzyl(3S,5S)-3-fluoro-5-((4-(2-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(30 mg, 0.04 mmol) in dichloromethane (1 mL) was added 33% HBr in aceticacid (0.5 mL) and stirred for 0.5 h at rt. The solvent was removed undervacuum. The residue was purified by Prep-HPLC to afford the titlecompound (12.9 mg, 53.2% yield) as a white solid.

Example 741-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 277 & Compound 278

Step 1: 1-(tert-Butyl) 3-methyl5-((methylsulfonyl)oxy)piperidine-1,3-dicarboxylate

A solution of 1-tert-butyl 3-methyl5-hydroxypiperidine-1,3-dicarboxylate (1.0 g, 3.86 mmol), triethylamine(1.6 mL, 11.53 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.4 mL, 5.17 mmol) at 0° C. and stirred for 1 h atrt. The reaction mixture was quenched with water and extracted withethyl acetate and the organic layers were combined. The organic layerwas washed by brine and dried over anhydrous sodium sulfate andconcentrated under vacuum to afford the title compound (1.2 g, 83%yield) as colorless oil. LCMS (ESI): [M+H−56]⁺=282.1.

Step 2: 1-(tert-Butyl) 3-methyl 5-azidopiperidine-1,3-dicarboxylate

A solution of 1-(tert-Butyl) 3-methyl5-((methylsulfonyl)oxy)piperidine-1,3-dicarboxylate (1.38 g, 3.68 mmol)and sodium azide (360 mg, 5.54 mmol) in N,N-dimethylformamide (16 mL)was stirred for 4 h at 80° C. The reaction was quenched with water andextracted with ethyl acetate. The combined organic was washed with brineand the organic layer was concentrated under vacuum to afford the titlecompound (1.0 g, 86% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=285.2.

Step 3: 1-(tert-Butyl) 3-methyl 5-aminopiperidine-1,3-dicarboxylate

Under hydrogen, a mixture of 1-(tert-butyl) 3-methyl5-azidopiperidine-1,3-dicarboxylate (1.40 g, 3.45 mmol), 10% Pd/C (0.30g, 0.28 mmol) in methanol (30 mL) was stirred at for 2 h at rt. Afterfiltration, the filtration was concentrated under vacuum to afford thetitle compound (1.2 g, 94.3% yield) as colorless oil. LCMS (ESI):[M+H]⁺=259.1.

Step 4: 1-(tert-Butyl) 3-methyl5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylate

To a solution of sodium bicarbonate (1.05 g, 12.5 mmol) and1-(tert-Butyl) 3-methyl 5-aminopiperidine-1,3-dicarboxylate (1.0 g, 2.71mmol) in tetrahydrofuran (12.5 mL) was added benzyl chloroformate (0.7g, 4.1 mmol) dropwise and stirred at rt for 4 h. The reaction wasquenched with ice water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith methanol/dichloromethane (3%) to afford the title compound (0.86 g,76.8% yield) as a colorless oil. LCMS (ESI): [M+H−56]⁺=337.2

Step 5: tert-Butyl3-(((benzyloxy)carbonyl)amino)-5-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-(tert-butyl) 3-methyl5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylate (860 mg, 2.19mmol) in tetrahydrofuran (15 mL) was added sodium borohydride (210 mg,5.55 mmol) slowly at 0° C. The resulting solution was stirred at rt for24 h. The reaction was quenched with water and extracted with ethylacetate, the organic layers were combined. The organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by silica flash chromatography eluting withmethanol/dichloromethane (6%) to afford the title compound (650 mg,77.3% yield) as colorless oil. LCMS (ESI): [M+H]⁺=365.2

Step 6: tert-Butyl3-(((benzyloxy)carbonyl)amino)-5-(fluoromethyl)piperidine-1-carboxylate

A solution of tert-butyl3-(benzyloxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate(1.20 g, 3.29 mmol) in toluene (20 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (1.72 mL, 11.51 mmol) at 0° C. Thenpyridine-2-sulfonyl fluoride (1.10 g, 6.83 mmol) was added. Then thereach CHI was stirred at 50° C. for 16 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate, the organic layerswere combined. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica flashchromatography eluting with methanol/dichloromethane (6%) to afford thetitle compound (850 mg, 42.3% yield) as a colorless oil. LCMS (ESI):[M+H]⁺=367.2.

Step 7: tert-Butyl 3-amino-5-(fluoromethyl)piperidine-1-carboxylate

Under hydrogen, a mixture of tert-butyl3-(fluoromethyl)-5-(phenoxycarbonylamino)piperidine-1-carboxylate (700mg, 1.99 mmol), 10% Pd/C (155 mg, 0.15 mmol) in methanol (10 mL) wasstirred at rt for 24 h. After filtration, the filtration wasconcentrated under vacuum to afford the title compound (450 mg, 97.5%yield) as a white solid. LCMS (ESI): [M+H]⁺=233.2.

Step 8: tert-Butyl3-(fluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(450 mg, 0.82 mmol), tert-butyl3-amino-5-(fluoromethyl)piperidine-1-carboxylate (230 mg, 0.99 mmol),cesium fluoride (900 mg, 5.92 mmol) and N,N-diisopropylethylamine (90mg, 0.70 mmol) in dimethyl sulfoxide (11 mL) was stirred at 60° C. for16 h. The reaction mixture was diluted with water and extracted withethyl acetate. The organic layer was concentrated under vacuum. Theresidue was purified by silica flash chromatography eluting withmethanol/dichloromethane (5%) to afford the title compound (450 mg, 47%yield) as a brown solid. LCMS (ESI): [M+H]⁺=703.2

Step 9:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide&1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 277 & Compound 278

A solution of tert-Butyl3-(fluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(400 mg, 0.34 mmol) in dichloromethane (8 mL) was added 4 M HCl indioxane (12 mL, 48 mmol) dropwise and stirred at rt for 1 h. The solventwas concentrated under vacuum. The residue was purified by Prep-HPLC andChiral HPLC. After Chiral HPLC, two peaks were isolated out. The fastpeak was assigned isomer 1. The slow peak was assigned isomer 2.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 1, Compound 277) (7.8 mg, 3.7%) as a white solid, (rt=17.64 min,CHIRALPAKIG, 0.46*5 cm; 3 um; Hex(0.1% DEA):EtOH=50:50; 1.0 ml/min).Compound 277 & Compound 278 are enantiomers.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 2, Compound 278) (7.5 mg, 3.6%) as a white solid, (rt=4.293 min,CHIRALPAK IG, 0.46*5 cm; 3 um; Hex(0.1% DEA):EtOH=50:50; 1.0 ml/min).Compound 277 & Compound 278 are enantiomers.

Example 75N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methylphenyl)-1-phenylmethanesulfonamideCompound 279

The title compound was prepared according to example 42. This resultedin the title compound (20.3 mg, 40.4% yield) as a white solid.

Example 76N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methylphenyl)-1-phenylmethanesulfonamideCompound 280

The title compound was prepared according to example 40. This resultedin the title compound (22.3 mg, 44.9% yield) as a white solid.

Example 771-(2,4-Difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 281

The title compound was prepared according to example 42. This resultedin the title compound (8.5 mg, 34.3% yield) as a white solid.

Example 781-(2,6-Difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 282

The title compound was prepared according to example 42. This resultedin the title compound (12.1 mg, 48.8% yield) as a white solid.

Example 79N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-(2,6-difluorophenyl)methanesulfonamideCompound 283

The title compound was prepared according to example 40. This resultedin the title compound (10.3 mg, 20.6% yield) as a white solid.

Example 801-p-Tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

-   -   Compound 284

The title compound was prepared according to example 42. This resultedin the title compound (5.3 mg, 32.3% yield) as a white solid.

Example 811-(4-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureahydrochloride Compound 285

Step 1: Benzyl(3S,5S)-3-((4-(2-(4-aminophenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate

Under nitrogen, a mixture of benzyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(0.3 g, 0.71 mmol), 4-aminophenol (0.08 g, 0.71 mmol) and cesiumcarbonate (0.35 g, 1.07 mmol) in dimethyl sulfoxide (10 mL) was stirredat 100° C. for 1 h. The resulting solution was diluted with water,extracted with ethyl acetate, washed with brine, dried over Sodiumsulfate and concentrated. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (70%) toafford the title compound (337 mg, 92.9% yield) as a brown solid. LCMS(ESI): [M+H]⁺=515.2.

Step 2: Benzyl(3S,5S)-3-fluoro-5-((4-(2-(4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A solution of benzyl(3S,5S)-3-((4-(2-(4-aminophenoxy)-3-pyridyl)pyrimidin-2-yl)amino)-5-fluoro-piperidine-1-carboxylate(60 mg, 0.12 mmol), phenyl chloroformate (20 mg, 0.13 mmol) and pyridine(28 mg, 0.35 mmol) in dichloromethane (3 mL) was stirred at rt for 1 h.The solvent was concentrated under vacuum.4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (35 mg,0.13 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) was added tothe above residue in 1,4-dioxane (3 mL) and stirred at 100° C. for 5 hunder nitrogen. The solvent was concentrated under vacuum. The residuewas purified by silica flash chromatography eluting withdichloromethane/methanol (90:10) to afford the title compound (69 mg,72.7% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=814.3

Step 3:1-(4-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureahydrochloride Compound 285

A solution of benzyl benzyl(3S,5S)-3-fluoro-5-((4-(2-(4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(65 mg, 0.08 mmol) in dichloromethane (2 mL) was added 33% HBr in AceticAcid (1 mL) and stirred at rt for 1 h. The solvent was concentratedunder vacuum. The residue was purified by Prep-HPLC to afford the titlecompound (13.1 mg, 22.9% yield) as a yellow solid and as HCl salt.

Example 821-(3-((3-(2-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureahydrochloride Compound 286

The title compound was prepared according to example 81. This resultedin the title compound (39.6 mg, 37.5% yield) as a yellow solid and asHCl salt.

Example 83N-(4-((3-(2-((1-Azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride Compound 287 & Compound 288

The title compound was prepared according to example 38. AfterPrep-HPLC, two peaks were isolated out. The fast peak was assignedisomer 1. The slow peak was assigned isomer 2.

N-(4-((3-(2-((1-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride (isomer 1) (22.9 mg, 8% yield) as a white solid and as HClsalt.

N-(4-((3-(2-((1-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 2) (6.7 mg, 2.4% yield) as a white solid.

Example 841-o-Tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 290

The title compound was prepared according to example 42. This resultedin the title compound (11.1 mg, 33.8% yield) as a yellow solid.

Example 851-(3-Methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 291

The title compound was prepared according to example 42. This resultedin the title compound (10.8 mg, 43.6% yield) as a yellow solid.

Example 86N-(2,6-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-methylphenyl)-1-phenylmethanesulfonamideCompound 292

The title compound was prepared according to example 42. This resultedin the title compound (5.5 mg, 33.7% yield) as a white solid.

Example 87N-(2,6-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-methylphenyl)-1-(2,6-difluorophenyl)methanesulfonamideCompound 293

The title compound was prepared according to example 40. This resultedin the title compound (12.1 mg, 29.4% yield) as a white solid.

Example 881-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 294 & Compound 295

Step 1: 1-(tert-Butyl) 3-methyl5-((diphenylmethylene)amino)piperidine-1,3-dicarboxylate

Under hydrogen, a mixture of 1-(tert-butyl) 3-methyl5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylate (5.0 g, 12.74mmol) and 10% Pd/C (1.0 g, 0.94 mmol) in ethyl acetate (50 mL) wasstirred at 50° C. for 4 h. The solid was filtered out. After filtration,the filtrate was dried over anhydrous sodium sulfate and concentratedunder vacuum to afford 1-(tert-butyl) 3-methyl5-((diphenylmethylene)amino)piperidine-1,3-dicarboxylate as a brownsolid.

Under nitrogen, a mixture of 1-(tert-butyl) 3-methyl5-((diphenylmethylene)amino)piperidine-1,3-dicarboxylate (3.0 g, 11.62mmol), benzophenone imine (4.0 g, 22.07 mmol) and triethylamine (8.0 g,79.21 mmol) in 1,2-dichlorobenzene (20 mL) was stirred at 80° C. for 16h. The resulting mixture was concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (1/3) to afford the title compound (4 g, 66.9%yield) as brown oil. LCMS (ESI): [M+H]⁺=423.2

Step 4: 1-(tert-butyl) 3-Methyl5-((diphenylmethylene)amino)-3-methylpiperidine-1,3-dicarboxylate

Under nitrogen, to a solution of 1-(tert-butyl) 3-methyl5-((diphenylmethylene)amino)piperidine-1,3-dicarboxylate (2.8 g, 5.96mmol) in tetrahydrofuran (30 mL) was added 2.0 M lithiumdiisopropylamide (9.0 mL, 18 mmol) dropwise at −60° C. and stirred at−60° C. for 1 h. Then iodomethane (1.7 mL, 27.31 mmol) was addeddropwise at −60° C. and stirred at rt for 4 h. The reaction was quenchedwith sat. ammonium chloride. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated to afford the title compound (2.8 g,75.3% yield). LCMS (ESI): [M+H]⁺=437.2

Step 5: 1-(tert-Butyl) 3-methyl5-(((benzyloxy)carbonyl)amino)-3-methylpiperidine-1,3-dicarboxylate

A mixture of 1-(tert-butyl) 3-methyl5-((diphenylmethylene)amino)-3-methyl piperidine-1,3-dicarboxylate (2.8g, 5.46 mmol) and acetic acid (15 mL) in tetrahydrofuran (30 mL) andwater (30 mL) was stirred at rt for 2 h. The reaction mixture wasadjusted to pH=9 with sat. sodium bicarbonate. The resulting solutionwas extracted with ethyl acetate and the organic layers were combined.The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 1-(tert-butyl) 3-methyl5-amino-3-methylpiperidine-1,3-dicarboxylate (2.8 g, 94.4% yield) as abrown oil.

To a solution of 1-(tert-butyl) 3-methyl5-amino-3-methylpiperidine-1,3-dicarboxylate (2.8 g, 5.16 mmol), sodiumbicarbonate (1.6 g, 19.05 mmol) in tetrahydrofuran (25 mL) was addedbenzyl chloroformate (1.5 g, 8.79 mmol) and stirred at rt for 5 h. Theresulting solution was diluted with water, extracted with ethyl acetate,washed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by silica flash chromatography eluting withdichloromethane/methanol (96:4) to afford the title compound (1.8 g,81.8% yield) as colorless oil. LCMS (ESI): [M+H]⁺=407.2

Step 6: tert-Butyl5-(((benzyloxy)carbonyl)amino)-3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate

To a solution of 1-(tert-butyl) 3-methyl5-(((benzyloxy)carbonyl)amino)-3-methylpiperidine-1,3-dicarboxylate (1.8g, 4.43 mmol) in tetrahydrofuran (25 mL) was added sodium borohydride(500 mg, 13.22 mmol) at 0° C. The resulting solution was stirred at rtfor 24 h. The reaction was quenched with water. The resulting solutionwas extracted with ethyl acetate, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica flashchromatography eluting with dichloromethane/methanol (96:4) to affordthe title compound (1.7 g, 96.4% yield) as brown oil. LCMS (ESI):[M+H]⁺=379.2

Step 7: tert-Butyl5-((diphenylmethylene)amino)-3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate

Under hydrogen, a mixture of tert-butyl5-(benzyloxycarbonylamino)-3-(hydroxymethyl)-3-methyl-piperidine-1-carboxylate(1.7 g, 4.08 mmol) and 10% Pd/C (0.6 g) in ethyl acetate (50 mL) wasstirred at 50° C. for 16 h. The solids were filtered out. Afterfiltration, the filtrate was concentrated under vacuum to affordtert-butyl 5-amino-3-(hydroxymethyl)-3-methyl-piperidine-1-carboxylate(1.1 g, 96.8% yield) as a colorless oil.

Under nitrogen, a mixture of tert-butyl5-amino-3-(hydroxymethyl)-3-methy 1-piperidine-1-carboxylate (0.7 g,2.58 mmol), triethylamine (2 g, 13.41 mmol) and benzophenone imine (1.0g, 5.52 mmol) in 1,2-dichlorobenzene (12 mL) was stirred at 80° C. for16 h. The organic layer was concentrated under vacuum. The residue waspurified by silica flash chromatography eluting withdichloromethane/methanol (96:4) to afford the title compound (970 mg,78.3% yield) as yellow oil. LCMS (ESI): [M+H]⁺=409.2

Step 8: tert-Butyl5-((diphenylmethylene)amino)-3-methyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

To a solution of tert-butyl5-(benzhydrylideneamino)-3-(hydroxymethyl)-3-methyl-piperidine-1-carboxylate(980 mg, 2.04 mmol), triethylamine (0.87 mL, 6.23 mmol) indichloromethane (10 mL) was added methane sufonyl chloride (0.24 mL,3.06 mmol) at 0° C. and stirred at rt for 1 h. The resulting solutionwas diluted with water, extracted with ethyl acetate, washed with brine,dried over Sodium sulfate and concentrated. The residue was purified bysilica flash chromatography eluting with dichloromethane/methanol (96:4)to afford the title compound (850 mg, 84.2% yield) as a colorless solid.LCMS (ESI): [M+H]⁺=487.2

Step 9: tert-Butyl5-((diphenylmethylene)amino)-3-(fluoromethyl)-3-methylpiperidine-1-carboxylate

To a mixture of tert-butyl5-(benzhydrylideneamino)-3-methyl-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate(800 mg, 1.32 mmol) and triethylamine trihydrofluoride intetrahydrofuran (10 mL, 10 mmol) was stirred at 80° C. for 16 h. Theresulting solution was diluted with water, extracted with ethyl acetate,washed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by silica flash chromatography eluting withdichloromethane/methanol (98:2) to afford the title compound (300 mg,52.8% yield) as yellow oil. LCMS (ESI): [M+H]⁺=411.2

Step 10: tert-Butyl5-amino-3-(fluoromethyl)-3-methylpiperidine-1-carboxylate

To a mixture of tert-butyl5-(benzhydrylideneamino)-3-(fluoromethyl)-3-methyl-piperidine-1-carboxylate(490 mg, 1.19 mmol) and acetic acid (3 mL) in water (6 mL) andtetrahydrofuran (6 mL) was stirred at rt for 1 h. The solvent wasremoved under vacuum. The residue was purified by silica flashchromatography eluting with dichloromethane/methanol (88/12) to affordthe title compound (325 mg, 88% yield) as a white solid. LCMS (ESI):[M+H]⁺=247.2

Step 11: tert-Butyl3-(fluoromethyl)-3-methyl-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a mixture of tert-butyl5-amino-3-(fluoromethyl)-3-methylpiperidine-1-carboxylate (200 mg, 0.65mmol),1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(350 mg, 0.64 mmol), cesium fluoride (500 mg, 3.29 mmol) andN,N-diisopropylethylamine (250 mg, 1.93 mmol) in dimethyl sulfoxide (7mL) was stirred at 80° C. for 1 h. The resulting solution was dilutedwith water, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with dichloromethane/methanol (96:4) toafford the title compound (300 mg, 66.9% yield) as a white solid. LCMS(ESI): [M+H]⁺=717.2

Step 12:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide&1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 294 & Compound 295

To a solution of tert-butyl3-(fluoromethyl)-3-methyl-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(300 mg, 0.42 mmol) in dichloromethane (4 mL) was added 4 M HCl indioxane (1 mL) dropwise and stirred at rt for 1 h. The solvent wasremoved under vacuum. The residue was purified by Prep-HPLC and ChiralHPLC to afford the title compound. After Chiral HPLC, two peaks wereisolated out. The fast peak was assigned isomer 1. The slow peak wasassigned isomer 2.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 1) (34.1 mg, 13.2% yield) as a white solid, (rt=3.394 min, SFCCHIRALPAK AD-3 3*100 mm,3 um, IPA(0.1% DEA); 3 mL/min).

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(fluoromethyl)-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(isomer 2) (34.7 mg, 13.4% yield) as a white solid, (rt=3.879 min, SFCCHIRALPAK AD-3 3*100 mm,3 um, IPA(0.1% DEA); 2 mL/min).

Example 89N-(2-Fluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methoxyphenyl)-1-phenylmethanesulfonamideCompound 296

The title compound was prepared according to Example 40. This resultedin the title compound (9.9 mg, 9.4% yield) as a white solid.

Example 90N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-(p-tolyl)methanesulfonamideCompound 297

The title compound was prepared according to example 42. This resultedin the title compound (26.6 mg, 43.7% yield) as a white solid.

Example 91N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 298 & Compound 299 & Compound 300 & Compound 301

Step 1: 1-(tert-butyl) 3-Methyl 5-oxopiperidine-1,3-dicarboxylate

Under nitrogen, a solution of ethanedioyl dichloride (4 mL, 47 mmol) indichloromethane (200 mL) was added dimethyl sulfoxide (6.6 mL, 93 mmol)in dichloromethane (5 mL) at −78° C. The solution was stirred at −78° C.for 1 h. A solution of 1-tert-butyl 3-methyl5-hydroxypiperidine-1,3-dicarboxylate (3.0 g, 11.6 mmol) indichloromethane (10 mL) was added to the above solution at −78° C. Thesolution was stirred at −78° C. for 1.5 h. A solution of triethylamine(16 mL, 115 mmol) in dichloromethane (10 mL) was added at −78° C. Thesolution was stirred at rt for 16 h. The mixture was diluted with waterand extracted with dichloromethane. The organic layers were collected.The solution was concentrate under vacuum. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(1/3) to afford the title compound (2.1 g, 70.5% yield) as light brownoil. ¹H NMR (300 MHz, CDCl₃) δ 4.05 (s, 2H), 3.95-3.84 (m, 2H), 3.73 (s,3H), 3.16-3.03 (m, 1H), 2.82-2.57 (m, 2H), 1.48 (s, 9H).

Step 2: Methyl1-(tert-butoxymethyl)-5-methylene-piperidine-3-carboxylate

Under nitrogen, a solution of methyltriphenylphosphoniumbromide (12.0 g,34 mmol) in tetrahydrofuran (200 mL) was added potassiumtert-butoxide(3.8 g, 31 mmol). The mixture was stirred for 3 h at rt. Then a solutionof 1-(tert-butyl) 3-methyl 5-oxopiperidine-1,3-dicarboxylate (2.0 g, 7.8mmol) in tetrahydronfuran (10 ml) was added. The mixture was stirred for16 h at rt. The reaction was diluted with sat. ammonium chloride andextracted with ethyl acetate. The organic layer was combined. Theorganic layer was dried over sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (20%) to afford the title compound(1.5 g, 80% yield) as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.90 (d,J=2.1 Hz, 2H), 4.37-4.14 (m, 2H), 3.72 (s, 3H), 3.51-3.44 (m, 1H),3.20-3.02 (m, 1H), 2.69-2.54 (m, 2H), 2.46-2.34 (m, 1H), 1.48 (s, 9H).

Step 3: 5-(tert-Butyl) 7-methyl1,1-difluoro-5-azaspiro[2.5]octane-5,7-dicarboxylate

Under nitrogen, a solution of methyl1-(tert-butoxymethyl)-5-methylene-piperidine-3-carboxylate (2.13 g, 8.34mmol) in ethanol (28 mL) was added sodium iodide (0.45 g, 3.1 mmol) and(trifluoromethyl)trimethylsilane (4.32 g, 30 mmol). The mixture wasstirred for 16 h at 65° C. The mixture was diluted with water andextracted with ethyl acetate. The combined organic layer was dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby silica flash chromatography eluting with ethyl acetate/petroleumether (20%) to afford the title compound (1.5 g, 58.9% yield) as lightyellow oil. ¹H NMR (300 MHz, CDCl₃) δ 4.52-4.38 (brs, 1H), 3.84-3.80 (m,1H), 3.72 (s, 3H), 3.15-3.08 (m, 1H), 2.65-2.58 (m, 1H), 1.99-1.95 (m,1H), 1.62-1.59 (m, 1H), 1.48 (s, 9H), 1.31-1.15 (m, 2H).

Step 4:5-tert-Butoxycarbonyl-2,2-difluoro-5-azaspiro[2.5]octane-7-carboxylicacid

Into the solution of 5-(tert-butyl) 7-methyl1,1-difluoro-5-azaspiro[2.5]octane-5,7-dicarboxylate (1.5 g, 4.91 mmol)in tetrahydrofuran (30 mL) and water (6 mL) was added lithium hydroxidemonohydrate (780 mg, 19 mmol). The solution was stirred at rt for 3 h.The reaction was adjusted pH to 5 by hydrochloric acid (0.5 M). Themixture was extracted with ethyl acetate and the organic layers werecombined. The solution was dried over sodium sulfate and concentratedunder vacuum to afford the title compound (1.4 g, 97.8% yield) ascolorless oil. LCMS (ESI): [M+H−56]⁺=236.1.

Step 5: tert-Butyl7-(benzyloxycarbonylamino)-2,2-difluoro-5-azaspiro[2.5]octane-5-carboxylate

Into the solution of5-tert-butoxycarbonyl-2,2-difluoro-5-azaspiro[2.5]octane-7-carboxylicacid (900 mg, 3.1 mmol) in toluene (120 mL) was addedN,N-diisopropylethylamine (1.8 mL, 10 mmol) and diphenylphosphoryl azide(0.9 mL, 4.2 mmol). The solution was stirred at 110° C. for 2 h. Thenbenzyl alcohol (2.7 mL, 26 mmol) was added. The solution was stirred at110° C. for 2 h. The solution was diluted with water and extracted withethyl acetate. The combined solution was concentrated under vacuum. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (35%) to afford the title compound (640 mg,52.3% yield) as colorless oil. LCMS (ESI): [M+H]⁺=397.2

Step 6: tert-Butyl7-amino-2,2-difluoro-5-azaspiro[2.5]octane-5-carboxylate

Into the solution of tert-butyl7-(benzyloxycarbonylamino)-2,2-difluoro-5-azaspiro[2.5]octane-5-carboxylate(234 mg, 0.59 mmol) in methyl alcohol (40 mL) was added 10% Pd/C (20mg). The mixture was stirred at rt for 1 h under hydrogen. The solid wasfiltered out and the solution was concentrated under vacuum to affordthe title compound (140 mg, 90.4% yield) as colorless oil. LCMS (ESI):[M+H]⁺=263.1.

Step 7: tert-Butyl1,1-difluoro-7-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate

Under nitrogen, into the solution of1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(260 mg, 0.47 mmol) in dimethyl sulfoxide (2.5 mL) was added tert-butyl7-amino-2,2-difluoro-5-azaspiro[2.5]octane-5-carboxylate (150 mg, 0.57mmol), cesium fluoride (130 mg, 0.86 mmol) and N,N-diisopropylethylamine(0.3 mL, 1.8 mmol). The mixture was stirred at 80° C. for 2 h. Themixture was diluted with water and extracted with ethyl acetate and theorganic layer was combined. The solution was washed with water, driedover sodium sulfate, and concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (30%-90%) to afford the title compound. Twoisomers were isolated out. The fast peak was assigned as isomer 1 andthe slow peak was assigned as isomer 2.

tert-Butyl1,1-difluoro-7-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate(isomer 1) (190 mg, 54.9% yield) as a light yellow solid. LCMS (ESI):[M+H]⁺=733.1.

tert-Butyl1,1-difluoro-7-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate(isomer 2) (200 mg, 57.8% yield) as a light yellow solid. LCMS (ESI):[M+H]⁺=733.2.

Step 8:N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 298 & Compound 299

Into the solution of 5% trifluoroacetic acid in hexafluoroisopropanol(10 mL, 0.26 mmol) was added tert-butyl1,1-difluoro-7-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate(isomer 1 of Step 7) (190 mg, 0.26 mmol). The solution was stirred at rtfor 2 h. The solution was concentrated under vacuum. The residue waspurified with Prep-HPLC and Chiral HPLC to afford the title compound.The fast peak was assigned as isomer 1 and the slow peak was assigned asisomer 2.

N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 1, Compound 298) (28.4 mg, 17.3% yield) as a white solid,(rt=2.047 min, CHIRALPAKIG-3, 0.46×5 cm; 3 um, MtBE(0.1% DEA):EtOH=95:5,1.0 mL/min).

N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 2, Compound 299) (38.7 mg, 23.5% yield) as a white solid,(rt=3.114 min, CHIRALPAK IG-3, 0.46×5 cm; 3 um, MtBE(0.1%DEA):EtOH=95:5, 1.0 mL/min).

Step 8:N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 300 & Compound 301

Into the solution of 5% trifluoroacetic acid in hexafluoroisopropanol(10 mL, 0.26 mmol) was added tert-butyl1,1-difluoro-7-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate(isomer 2 of Step 7) (220 mg, 0.30 mmol). The solution was stirred at rtfor 2 h. The solution was concentrated under vacuum. The residue waspurified with Prep-HPLC and Chiral HPLC to afford the title compound.The fast peak was assigned as isomer 3 and the slow peak was assigned asisomer 4.

N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 3, Compound 300) (39.8 mg, 20.9% yield) as a white solid,(rt=3.013 min, CHIRALPAK IE-3, 0.46×5 cm; 3 um, hex(0.1%DEA):EtOH=50:50, 1.0 mL/min).

N-(4-((3-(2-((1,1-Difluoro-5-azaspiro[2.5]octan-7-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 4, Compound 301) (46.1 mg, 24.2% yield) as a white solid,(rt=3.906 min, CHIRALPAK IE-3, 0.46×5 cm; 3 um, hex(0.1%DEA):EtOH=50:50, 1.0 mL/min).

Example 92N-(4-((3-(2-((5-(Difluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 302 & Compound 303

Step 1: tert-Butyl 3-(benzyloxy)-5-formylpiperidine-1-carboxylate

To a solution of tert-butyl3-benzyloxy-5-(hydroxymethyl)piperidine-1-carboxylate (2.3 g, 7.16 mmol)and triethylamine (3.8 g, 37.62 mmol) in dimethyl sulfoxide (20 mL) wasadded sulfurtrioxide-pyridine complex (4.6 g, 28.9 mmol) at 0° C. andstirred at rt for 2 h. The resulting solution was diluted with water,extracted with ethyl acetate, washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96:4) to afford the title compound (1.1 g, 45.7% yield) as colorlessoil. LCMS (ESI): [M+H]⁺=320.2

Step 4: 1-(tert-Butyl) 3-methyl5-((diphenylmethylene)amino)-3-methylpiperidine-1,3-dicarboxylate

Under nitrogen, to a solution of tert-butyl3-benzyloxy-5-formyl-piperidine-1-carboxylate (1000 mg, 3.13 mmol) indichloromethane (20 mL) was added diethylaminosulfur trifluoride (1700mg, 10.55 mmol) in dichloromethane (3 mL) dropwise at 0° C. and stirredfor 1 h at the same temperature. The reaction mixture was diluted withethyl acetate and quenched with sat. sodium bicarbonate. The resultingsolution was extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with dichloromethane/methanol (99:1) toafford the title compound (450 mg, 40% yield) as colorless oil. LCMS(ESI): [M+H]⁺=342.2

Step 5: tert-Butyl 3-(difluoromethyl)-5-hydroxypiperidine-1-carboxylate

Under hydrogen, a mixture of tert-butyl3-benzyloxy-5-(difluoromethyl)piperidine-1-carboxylate (450 mg, 1.32mmol) and 10% Pd/C (150 mg, 0.14 mmol) in methyl alcohol (10 mL) wasstirred at rt for 4 h. The solid was filtered out After filtration, thefiltrate was dried over anhydrous sodium sulfate and concentrated undervacuum to afford the title compound (330 mg, 89.7% yield) as brown oil.LCMS (ESI): [M+H]⁺=252.1

Step 6: tert-Butyl 3-amino-5-(difluoromethyl)piperidine-1-carboxylate

A solution of tert-butyl3-(difluoromethyl)-5-hydroxy-piperidine-1-carboxylate (330 mg, 1.18mmol), Triethylamine (0.03 mL, 0.25 mmol) in dichloromethane (8 mL) wasadded methanesulfonyl chloride (0.02 mL, 0.22 mmol) at 0° C. and stirredat rt for 1 h. The resulting solution was diluted with water, extractedwith ethyl acetate, washed with brine, dried over sodium sulfate andconcentrated to afford tert-butyl3-(difluoromethyl)-5-methylsulfonyloxy-piperidine-1-carboxylate (0.34 g,78.6% yield) as a white solid.

A solution of tert-butyl3-(difluoromethyl)-5-methylsulfonyloxy-piperidine-1-carboxylate (280 mg,0.85 mmol) and sodium azide (170 mg, 2.61 mmol) in N,N-dimethylformamide(4 mL) was stirred for 4 h at 80° C. The reaction was quenched withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated to afford tert-butyl3-azido-5-(difluoromethyl)piperidine-1-carboxylate (0.22 g, 89% yield)as a brown oil.

Under hydrogen, a mixture of tert-butyl3-azido-5-(difluoromethyl)piperidine-1-carboxylate (310 mg, 1.07 mmol)and 10% Pd/C (200 mg, 0.19 mmol) in methanol (10 mL) was stirred at rtfor 16 h. The solid was filtered out. After filtration, the filtrationwas concentrated under vacuum to afford the title compound (270 mg,91.1% yield) as brown oil. LCMS (ESI): [M+H]⁺=251.2

Step 7: tert-Butyl3-(difluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a mixture of tert-butyl3-amino-5-(difluoromethyl)piperidine-1-carboxylate (260 mg, 0.93 mmol),1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(375 mg, 0.68 mmol), cesium fluoride (510 mg, 3.36 mmol) andN,N-diisopropylethylamine (280 mg, 2.17 mmol) in dimethyl sulfoxide (6mL) was stirred at 80° C. for 1 h. The resulting solution was dilutedwith water, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with dichloromethane/methanol (96:4) toafford the title compound (380 mg, 69.7% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=721.2

Step 8:N-(4-((3-(2-((5-(Difluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 302 & Compound 303

To a solution of tert-butyl3-(difluoromethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(260 mg, 0.36 mmol) in dichloromethane (3 mL) was added 4 M HCl indioxane (5 mL) and stirred at rt for 1 h. The solvent was concentratedunder vacuum. The residue was purified by Prep-HPLC and Chiral HPLC toafford the title compound. After Chiral HPLC, two peaks were isolatedout. The fast peak was assigned isomer 1. The slow peak was assignedisomer 2.

N-(4-((3-(2-((5-(Difluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 1) (105.2 mg, 45.7% yield) as a white solid, (rt=3.361 min,CHIRALPAK AD-3, 3*100 mm,3 um, IPA(0.1% DEA); 3 mL/min).

N-(4-((3-(2-((5-(Difluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 2) (84.8 mg, 37.6% yield) as a white solid, (rt=3.764 min,CHIRALPAK AD-3, 3*100 mm,3 um, IPA(0.1% DEA); 3 mL/min).

Example 931-(4-Methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 304

Step 1:1-(4-Bromophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a mixture of2,3,6-trifluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(0.25 g, 0.69 mmol) and triethylamine (0.21 g, 2.06 mmol) indichloromethane (2 mL) was added 4-bromobenzylsulfonyl chloride (0.55 g,2.06 mmol), the mixture was stirred for 2 h at rt. The resultingsolution was diluted with water and extracted with ethyl acetate, theorganic layers was washed with brine and dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate(l/2) to afford the titlecompound (280 mg, 68.3% yield) as a brown solid. LCMS (ESI):[M+H]⁺=597.1.

Step 2:1-(4-Methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

A mixture of1-(4-bromophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(0.28 g, 0.47 mmol), cesium carbonate (0.46 g, 1.41 mmol),allylpalladium chloride dimer (0.02 g, 0.05 mmol) and Rockphos (0.04 g,0.09 mmol) in methyl alcohol (0.50 mL) and toluene (2.5 mL) was stirredat 85° C. for 2 h under nitrogen. The resulting solution was dilutedwith water and extracted with ethyl acetate, the solvent was removedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (1:1) to afford the titlecompound (190 mg, 73.9% yield) as a dark yellow solid. LCMS (ESI):[M+H]⁺=549.2.

Step 3:1-(4-Methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 304

The title compound was prepared according to example 42. This resultedin the title compound (25.8 mg, 34.7% yield) as a white solid.

Example 94N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-6-methylphenyl)-1-(p-tolyl)methanesulfonamideCompound 305

The title compound was prepared according to example 42. This resultedin the title compound (23.6 mg, 32.0% yield) as a white solid.

Example 95N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamideCompound 306 & Compound 307 & Compound 308

Step 1: Ethyl 3-fluoro-4-oxocyclohexane-1-carboxylate

Under nitrogen, a solution of ethyl 4-oxocyclohexanecarboxylate (10 mL,62.8 mmol) in methyl alcohol (200 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (30 g, 94 mmol) and con. sulfuric acid (0.1 mL,1.84 mmol). The resulting solution was stirred for 16 h at 60° C. Thereaction was quenched with brine and extracted with ethyl acetate. Thesolvent was removed under vacuum. The crude product was dissolved indichloromethane (50 mL). And 2,2,2-trifluoroacetic acid (20 mL) wasadded. The resulting solution was stirred for 2 h at rt. The solvent wasremoved. The residue was dissolved in ethyl acetate and washed with sat.sodium bicarbonate. The solvent was removed. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(1/10) to afford the title compound (11.2 g, 94.8% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.38-5.08 (m, 1H), 4.19-4.08 (m, 2H),3.11-2.95 (m, 1H), 2.63-2.52 (m, 1H), 2.52-2.13 (m, 2H), 2.12-1.89 (m,1H), 1.92-1.59 (m, 1H), 1.22 (dt, J=13.5, 7.1 Hz, 3H).

Step 2: Ethyl 4-(dimethylamino)-3-fluorocyclohexane-1-carboxylate

A solution of ethyl 3-fluoro-4-oxo-cyclohexanecarboxylate (10.0 g, 53.1mmol) in 1,2-dichloroethane (150 mL) was added N,N-dimethylamine (35 mL,70 mmol) and sodium triacetoxyborohydride (17 g, 80.2 mmol). Then aceticacid (3 mL) was added. The resulting solution was stirred for 12 h atrt. The reaction was quenched with sat sodium carbonate and extractedwith ethyl acetate. The solvent was removed under vacuum. The residuewas purified by silica flash chromatography eluting withdichloromethane/methanol (5/1) to afford the title compound (9.5 g,82.3% yield) as yellow oil. LCMS (ESI, m/z): [M+H]⁺=218.2.

Step 3: 4-(Dimethylamino)-3-fluorocyclohexane-1-carboxylic acidhydrochloride

A solution of ethyl 4-(dimethylamino)-3-fluorocyclohexane-1-carboxylate(9.5 g, 46.7 mmol) in 1,4-dioxane (50 mL) was added 4 M HCl in dioxane(50 mL) and stirred for 24 h at 100° C. The solvent was removed undervacuum to afford the title compound (10 g, 94.8% yield) as a yellowsolid and as HCl salt. LCMS (ESI, m/z): [M+H]⁺=190.1.

Step 4: Benzyl (4-(dimethylamino)-3-fluorocyclohexyl)carbamate

Under nitrogen, a solution of4-(dimethylamino)-3-fluoro-cyclohexanecarboxylic acid hydrochloride(10.0 g, 44.3 mmol) in toluene (200 mL) was added diphenylphosphorylazide (11 mL, 51.1 mmol) and N,N-diisopropylethylamine (40 mL, 241.9mmol) at rt and then stirred for 4 h at 100° C. Then the solution wascooled to 50° C. Benzyl alcohol (20 mL, 193 mmol) was added and stirredfor 2 h at 100° C. The reaction was quenched with brine and extractedwith ethyl acetate. The residue was purified by silica flashchromatography eluting with dichloromethane/menthol (5/1) and reversephase (ACN/10 mM NH₄HCO₃) to afford title compound (4.6 g, 35.3% yield)as a yellow oil. LCMS (ESI, m/z): [M+H]⁺=295.1.

Step 5: 2-Fluoro-N,N-dimethylcyclohexane-1,4-diamine hydrochloride

Under hydrogen, a mixture of benzyl(4-(dimethylamino)-3-fluorocyclohexyl)carbamate (2.0 g, 6.79 mmol) and10% Pd/C (0.2 g) in methyl alcohol (30 mL) was added con. HCl (0.1 mL)and stirred for 2 h at rt. The solids were filtered out. The filtratewas concentrated under vacuum to afford the title compound (1.2 g, 89.8%yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=161.1.

Step 6:N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide&N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride Compound 306 & Compound 307 & Compound 308

Under nitrogen, a solution of1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(2.0 g, 3.63 mmol), 2-fluoro-N,N-dimethylcyclohexane-1,4-diaminehydrochloride (857 mg, 4.36 mmol), caesium fluoride (1.1 g, 7.27 mmol),N,N-diisopropylethylamine (1.8 mL, 10.9 mmol) in dimethyl sulfoxide (20mL) was stirred for 2 h at 90° C. The reaction was quenched with brineand extracted with ethyl acetate. The solvent was removed under vacuum.The residue was purified by silica flash chromatography eluting withdichloromethane/methanol (10/1). The crude product was further purifiedby Prep-HPLC and Chiral HPLC.

After Prep-HPLC, two components were isolated out. The first componentwas assigned as isomer 1 (mixture of enantiomers). The second componentwas separated by Chiral HPLC. After Chiral HPLC, the fast peak wasassigned as isomer 2 and the slow peak was assigned as isomer 3.

N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride as mixture (isomer 1, Compound 307) (666.9 mg, 27.5%yield).

N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 2, Compound 306) (31.5 mg, 1.4% yield) as white solid, (rt=1.332min, CHIRALPAK IA-3, 0.46×5 cm; 3 um, (Hex:DCM=3:1)(0.1% DEA&0.1%FA):IPA=80:20, 1.0 ml/min). Compound 306 and Compound 308 areenantiomers.

N-(4-((3-(2-((4-(Dimethylamino)-3-fluorocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(isomer 3, Compound 308) (36.1 mg, 1.6% yield) as white solid, (rt=2.518min, CHIRALPAK IA-3, 0.46×5 cm; 3 um, (Hex:DCM=3:1)(0.1% DEA&0.1%FA):IPA=80:20, 1.0 ml/min). Compound 306 and Compound 308 areenantiomers.

Example 96N-(4-((3-(2-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)propane-1-sulfonamideCompound 309

The title compound was prepared according to example 38. This resultedin the title compound (43.2 mg, 16.6% yield) as a white solid.

Example 96aN-(4-((3-(2-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-3,3-difluorobutane-1-sulfonamideCompound 310

The title compound was prepared according to Example 38. This resultedin the title compound (56.5 mg, 24.2% yield) as a white solid.

Example 97N-(2,5-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-methylphenyl)-1-(p-tolyl)methanesulfonamideCompound 311

Step 1: 2-Bromo-3,6-difluorophenol

A solution of 2,5-difluorophenol (5.8 g, 45 mmol) and isopropylamine(3.3 mL) in tetrahydrofuran (120 mL) was stirred at −40° C. Then1-bromo-2,5-pyrrolidinedione (8.3 g, 47 mmol) was added and stirred at−40° C. for 2 h. The reaction mixture was diluted with 1 M hydrochloricacid (20 mL). The resulting solution was extracted with ethyl acetateand the organic layers were combined. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (0-5%) to afford the title compound (8.0 g,85.3% yield) as a yellow oil. LCMS (ESI): [M−H]⁻⁼207.2.

Step 2: 2-Bromo-3,6-difluoro-4-nitrophenol

Under nitrogen, a solution of 2-bromo-3,6-difluoro-phenol (3.2 g, 15mmol) in dichloromethane (30 mL) was added nitric acid (1.5 mL, 14 mmol)in sulfuric acid (3 mL) at 0° C. and stirred for 2 h. The reaction wasquenched with ice water and extracted with dichloromethane and theorganic layers were combined. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica flash chromatography eluting with ethyl acetate/petroleumether (0-5%) to afford the title compound (2 g, 51.4% yield) as brownoil. LCMS (ESI): [M−H]⁻=252.2.

Step 3: 2-(Benzyloxy)-3-bromo-1,4-difluoro-5-nitrobenzene

A solution of 2-bromo-3,6-difluoro-4-nitro-phenol (1.9 g, 7.48 mmol) andpotassium carbonate (2.6 g, 19 mmol) in N,N-dimethylacetamide (40 mL)was stirred at rt for 0.5 h. Then benzyl bromide (1.6 g, 9.4 mmol) wasadded and stirred at rt for 1.5 h. The solvent was concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (1%) to afford the title compound(2.1 g, 81.6% yield) as a light yellow solid.

Step 4: 2-(Benzyloxy)-1,4-difluoro-3-methyl-5-nitrobenzene

Into a solution of 2-benzyloxy-3-bromo-1,4-difluoro-5-nitro-benzene (1g, 2.91 mmol) in toluene (10 mL), water (1 mL) was addedmethylboronicacid (523 mg, 8.74 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (213 mg,0.29 mmol) and potassium fluoride (506 mg, 8.72 mmol), the mixture wasstirred at 90° C. for 2 h under nitrogen. The reaction mixture wasdiluted with water and extracted with ethyl acetate and the organiclayers were combined. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(0-5%) to afford the title compound (700 mg, 86.3% yield) as yellow oil.

Step 5: 4-Amino-3,6-difluoro-2-methylphenol

Into a solution of 2-benzyloxy-1,4-difluoro-3-methyl-5-nitro-benzene(800 mg, 2.86 mmol) in methanol (7 mL) was added 10% Pd/C (80 mg), themixture was stirred at rt for 1.5 hours under hydrogen. The solids werefiltered out. The solvent was removed under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (20%) to afford the title compound (254 mg, 55%yield) as a purple solid. LCMS (ESI): [M+H]⁺=160.2.

Step 6:N-(2,5-Difluoro-4-((3-(2-(((3S,5S)-5-fluoro-5-methylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3-methylphenyl)-1-(p-tolyl)methanesulfonamideCompound 311

The title compound was prepared according to example 42. This resultedin the title compound (26.0 mg, 22.6% yield) as a white solid.

Example 981-(4-(Methylsulfonyl)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 312

Step 1:1-(4-Bromophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a mixture of2,3,6-trifluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(500 mg, 1.37 mmol) in pyridine (3 mL) was added 4-bromobenzylsulfonylchloride (820 mg, 3.04 mmol), the mixture was stirred for 1 h at rt. Theresulting solution was diluted with water, extracted with ethyl acetate,washed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (1:1) to afford the title compound (450 mg,54.9% yield) as a brown solid. LCMS (ESI): [M+H]⁺=597.0.

Step 2:1-(4-(Methylthio)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

A mixture of1-(4-bromophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(200 mg, 0.33 mmol), sodium thiomethoxide (40 mg, 0.57 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol) andN,N-diisopropylethylamine (130 mg, 0.14 mmol) in toluene (2 mL) wasstirred at 110° C. for 2 h under nitrogen. The resulting solution wasdiluted with water, extracted with ethyl acetate and the organic layerswere combined. The residue was purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (1/4) to afford the titlecompound (180 mg, 95.2% yield) as a white solid. LCMS (ESI):[M+H]⁺=565.1.

Step 3:1-(4-(Methylsulfonyl)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a mixture of1-(4-(methylthio)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(150 mg, 0.27 mmol) in dichloromethane (2 mL) was added3-chloroperoxybenzoic acid (150 mg, 0.87 mmol), the mixture was stirredfor 1 h at rt. The resulting solution was diluted with water, extractedwith ethyl acetate and the organic layer was concentrated under vacuum.The crude would be directly used in the next step without purification.LCMS (ESI): [M+H]⁺=629.0

Step 4: Benzyl(3S,5S)-3-fluoro-5-((4-(2-(2,3,5-trifluoro-4-(((4-(methylsulfonyl)phenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of1-(4-(methylsulfonyl)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(150 mg, 0.24 mmol), benzyl(3S,5S)-3-amino-5-fluoro-piperidine-1-carboxylate (66 mg, 0.26 mmol),caesium fluoride (108 mg, 0.71 mmol) and N,N-diisopropylethylamine (108mg, 0.84 mmol) in dimethyl sulfoxide (2 mL) was stirred at 80° C. for 2h under nitrogen. The resulting solution was diluted with water,extracted with ethyl acetate, washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (3/1) toafford the title compound (150 mg, 78.5% yield) as a white solid. LCMS(ESI): [M+H]⁺=801.2

Step 5:1-(4-(Methylsulfonyl)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 312

A mixture of benzyl(3S,5S)-3-fluoro-5-((4-(2-(2,3,5-trifluoro-4-(((4-(methylsulfonyl)phenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(160 mg, 0.2 mmol) in dichloromethane (1 mL) was added 33% HBr in aceticacid (0.5 mL) and stirred at rt for 1 h. The solvent was removed undervacuum. The crude product was purified by Prep-HPLC to afford the titlecompound (43.1 mg, 32.4% yield) as a white solid.

Example 99N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-phenylethane-1-sulfonamidehydrochloride Compound 313 & Compound 314

Step 1:N-(2,3-Difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N-(methoxymethyl)-1-phenylmethanesulfonamide

Into the solution ofN-(2,3-difluoro-5-methyl-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)-1-phenyl-methanesulfonamide(610 mg, 1.2 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethylamine (0.6 mL, 3.6 mmol) and chloromethyl methylether (0.14 mL, 1.9 mmol). The solution was stirred at rt for 1.5 h. Thesolution was diluted with water and extracted with dichloromethane. Theorganic solution was concentrated under vacuum. The residue was purifiedby silica flash chromatography eluting with ethyl acetate/petroleumether (0%-30%) to afford the title compound (660 mg, 90% yield) as alight yellow solid. LCMS (ESI): [M+H]⁺=559.1.

Step 2:N-(2,3-Difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N-(methoxymethyl)-1-phenylethane-1-sulfonamide

Into the solution ofN-(2,3-difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N-(methoxymethyl)-1-phenylmethanesulfonamide(660 mg, 1.2 mmol) in tetrahydrofuran (20 mL) was added 1 Mlithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.68 mL, 1.7 mmol)at −70° C. The solution was stirred for 1 h at −70° C. Iodomethane (171mg, 1.2 mmol) in tetrahydrofuran (5 mL) was added at −70° C. Thereaction was allowed to warm to rt slowly, The solution was stirred for3 h at rt. The reaction was quenched with sat ammonium chloride andextracted with ethyl acetate. The solution was dried over sodium sulfateand concentrated under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (10%-40%) toafford the title compound (540 mg, 79.8% yield) as a light yellow solid.LCMS (ESI): [M+H]⁺=573.1.

Step 3:N-(2,3-Difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylethane-1-sulfonamide

A solution ofN-(2,3-difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-N-(methoxymethyl)-1-phenylethane-1-sulfonamide(540 mg, 0.94 mmol) in 2,2,2-trifluoroacetic acid (10 mL) and water (1mL) was stirred at rt for 3 h. The solution was diluted with water andadjusted to pH=9 with sodium carbonate. The mixture was extracted withdichloromethane and the organic layer was combined. The solution wasdried over sodium sulfate and concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (0%-40%) to afford the title compound (410 mg,82.3% yield) as a light yellow solid. LCMS (ESI): [M+H]⁺=529.1.

Step 4:N-(2,3-Difluoro-5-methyl-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylethane-1-sulfonamide

Into the solution ofN-(2,3-difluoro-5-methyl-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylethane-1-sulfonamide(410 mg, 0.78 mmol) in dichloromethane (20 mL) was added3-chloroperoxybenzoic acid (475 mg, 2.3 mmol). The solution was stirredat rt for 2.5 h. The reaction was quenched with sat sodium sulfite andextracted with dichloromethane. The organic layer was washed with sat.sodium bicarbonate, dried over sodium sulfate and concentrated undervacuum to afford the title compound (435 mg, 99% yield) as a lightyellow solid. LCMS (ESI): [M+1]⁺=561.1.

Step 5: Benzyl(3S,5S)-3-((4-(2-(2,3-difluoro-6-methyl-4-((1-phenylethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate

Under nitrogen, into the solution ofN-(2,3-difluoro-5-methyl-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-phenylethane-1-sulfonamide(435 mg, 0.78 mmol) in dimethyl sulfoxide (4 mL) was added benzyl(3S,5S)-3-amino-5-fluoro-piperidine-1-carboxylate hydrochloride (280 mg,0.97 mmol), cesium fluoride (236 mg, 1.55 mmol) andN,N-diisopropylethylamine (0.5 mL, 3.0 mmol). The mixture was stirred at80° C. for 16 h. The mixture was diluted with ethyl acetate and water.The mixture was extracted with ethyl acetate and the organic layers werecombined. The organic layer was washed with water, dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (40%-60%) to afford the title compound (430 mg,75.6% yield) as a light yellow solid. LCMS (ESI): [M+H]⁺=733.2.

Step 6:N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-phenylethane-1-sulfonamidehydrochloride &N-(2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-phenylethane-1-sulfonamideCompound 313 & Compound 314

Into the solution of benzyl(3S,5S)-3-((4-(2-(2,3-difluoro-6-methyl-4-((1-phenylethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate(430 mg, 0.59 mmol) in dichloromethane (10 mL) was added 33%hydrobromicacid in acetic acid (2 mL). The solution was stirred at rtfor 2 h. The mixture was concentrated under vacuum. The residue waspurified with Prep-HPLC and Chiral-HPLC to afford the title compound.The fast peak was assigned as isomer 1. The slow peak was assigned asisomer 2.

N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-phenylethane-1-sulfonamidehydrochloride (isomer 1, Compound 313) (50.1 mg, 13.4% yield) as a whitesolid and as HCl salt, (rt=1.712 min, CHIRALPAK IC-3, 0.46×5 cm; 3 um,(Hex:DCM=3:1)(0.1% DEA):EtOH=80:20, 1.0 mL/min).

N-(2,3-Difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-5-methylphenyl)-1-phenylethane-1-sulfonamide(isomer 2, Compound 314) (58.7 mg, 16.7% yield) as a white solid,(rt=2.099 min, CHIRALPAK IC-3, 0.46×5 cm; 3 um, (Hex:DCM=3:1)(0.1%DEA):EtOH=80:20, 1.0 mL/min).

Example 1001-(4-Cyclopropylphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 315

Step 1:1-(4-Cyclopropylphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide

To a mixture of1-(4-bromophenyl)-N-(2,3,6-trifluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(300 mg, 0.50 mmol) and di-iodobis(tri-t-butylphosphino)dipalladium(I)(44 mg, 0.06 mmol) in toluene (3 mL) was added bromo(cyclopropyl)zinc (4mL, 2 mmol) for 10 min at rt under nitrogen, the mixture was stirred for2 h at rt. The reaction was quenched with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (5%-20%) toafford the title compound (261 mg, 93% yield) as a white solid. LCMS(ESI): [M+H]⁺=559.10.

Step 3:1-(4-Cyclopropylphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 315

The title compound was prepared according to example 98. This providesthe title compound (39 mg, 40.8% yield) as a white solid.

Example 1011-(4-Fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 316

The title compound was prepared according to example 64. This providesthe title compound (28 mg, 27.1% yield) as a white solid.

Example 1021-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide&1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 317 & Compound 318 & Compound 319

Step 1: 1-(tert-Butyl) 3-methyl 5-methoxypiperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-methyl5-hydroxypiperidine-1,3-dicarboxylate (1.0 g, 3.86 mmol) inN,N-dimethylformamide (10 mL) was added sodium hydride (0.3 g, 7.50mmol) at 0° C. and stirred for 0.5 h at the same temperature. Theniodomethane (0.6 mL, 9.64 mmol) was added and stirred at rt for 1 h. Thereaction was quenched with sat. ammonium chloride and extracted withethyl acetate. The organic layers were washed with brine andconcentrated under vacuum to afford the title compound (1 g, 85.4%yield) as a white solid. LCMS (ESI): [M+H]⁺=274.2

Step 2: 1-(tert-butoxycarbonyl)-5-methoxypiperidine-3-carboxylic acid

To a solution of 1-(tert-butyl) 3-methyl5-methoxypiperidine-1,3-dicarboxylate (1.0 g, 3.66 mmol) in methylalcohol (10 mL) and water (2 mL) was added potassium carbonate (1.0 g,7.24 mmol) at rt. The mixture was stirred under 80° C. for 16 h. Theresulting solution was adjust pH to 5 with 1M HCl. The resultingsolution was extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated to afford the title compound (1.1 g,92.8% yield) as yellow oil. LCMS (ESI): [M+H]⁺=260.1

Step 3: tert-Butyl3-(((benzyloxy)carbonyl)amino)-5-methoxypiperidine-1-carboxylate

Under nitrogen, a mixture of1-(tert-butoxycarbonyl)-5-methoxypiperidine-3-carboxylic acid (1.0 g,3.86 mmol), diphenylphosphoryl azide (1.5 g, 5.45 mmol) andtriethylamine (1.1 mL, 5.36 mmol) in toluene (10 mL) was stirred for 2 hat 100° C. Then benzyl alcohol (4 mL, 38.67 mmol) was added at 50° C.and stirred at 100° C. for 2 h. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with dichloromethane/methanol (99:1) toafford the title compound (0.70 g, 39.8% yield) as brown oil. LCMS(ESI): [M+H]⁺=365.2.

Step 4: tert-Butyl 3-amino-5-methoxypiperidine-1-carboxylate

Under hydrogen, a mixture of tert-butyl3-(((benzyloxy)carbonyl)amino)-5-methoxypiperidine-1-carboxylate (700mg, 1.34 mmol) and 10% Pd/C (360 mg, 0.34 mmol) in ethyl acetate (15 mL)was stirred at 50° C. for 3 h. The solids were filtered out Afterfiltration, the solvent was concentrated under vacuum to afford thetitle compound (430 mg, 97.2% yield) as black oil. LCMS (ESI):[M+H]⁺=231.2

Step 5:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 317 & Compound 318 & Compound 319

The title compound was prepared according to example Compound 328 &Compound 329 & Compound 331.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(36.9 mg, 51.6% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(Compound 317) (30.5 mg, 42.7% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(Compound 318) (30.3 mg, 42.5% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-methoxypiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamide(Compound 319) (47.1 mg, 57% yield) as a white solid.

Example 1031-(2,4-Difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 320

The title compound was prepared according to example 64. This providesthe title compound (43 mg, 35.5% yield) as a white solid.

Example 1041-(4-Cyanophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5R)-5-(fluoromethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 321

The title compound was prepared according to example 64. This providesthe title compound (20.1 mg, 23.3% yield) as a white solid.

Example 1051-(4-Fluoro-2-methylphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 322

The title compound was prepared according to example 40. This resultedin the title compound (56.9 mg, 46.4% yield) as a white solid.

Example 106N-(6-Chloro-2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 323

The title compound was prepared according to example 40. This resultedin the title compound (22 mg, 39.3% yield) as a white solid.

Example 107N-(4-((3-(2-((5-Cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamide& Compound 324 & Compound 325 & Compound 326 & Compound 327

Step 1: 5-Cyclopropylpyridin-3-amine

Under nitrogen, a mixture of 5-bromo-3-pyridinamine (5.0 g, 28.9 mmol),cyclopropylboronicacid (5.0 g, 58.21 mmol),tetrakis(triphenylphosphine)palladium (1.8 g, 1.56 mmol), cesiumcarbonate (2.9 g, 89.01 mmol) in water (5 mL) and 1,4-dioxane (45 mL)was stirred at 100° C. for 16 h. The reaction mixture was diluted withwater. The resulting solution was diluted with water, extracted withethyl acetate, washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (1:1) to afford the titlecompound (4.2 g, 97.5% yield) as a brown solid. LCMS (ESI):[M+H]⁺=135.1.

Step 2: tert-Butyl (5-cyclopropylpyridin-3-yl)carbamate

To a solution of 5-cyclopropylpyridin-3-amine (3.40 g, 22.81 mmol) andsodium bis(trimethylsilyl)amide (25 mL, 50 mmol) in tetrahydrofuran (50mL) was added di-tert-butyldicarbonate (1.4 g, 64.15 mmol) and stirredat 25° C. for 16 h. The reaction was quenched with saturated ammoniumchloride solution. The resulting solution was extracted with ethylacetate and the organic layers were combined. The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product was dissolved in methanol (20 mL) and tetrahydrofuran (40mL) was added sodium hydroxide solution (20 mL, 1 M) dropwise andstirred at rt for 5 h. The resulting solution was extracted with ethylacetate and the organic layers were combined. The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by silica flash chromatography eluting with ethylacetate/petroleum ether (70:30) to afford the title compound (4.9 g,73.4% yield) as a brown solid. LCMS (ESI): [M+H]⁺=235.1

Step 3: tert-Butyl (5-cyclopropylpiperidin-3-yl)carbamate

A mixture of tert-butyl N-(5-cyclopropyl-3-pyridyl)carbamate (5.0 g,10.67 mmol), Rh/C (550 mg, 0.26 mmol), platinum(Iv) oxide (1.0 g, 4.4mmol) and acetic acid (500 mL) was stirred at 70° C. under hydrogen (15atm) for 24 h. After cooling to rt, the solids were filtered. And thefiltrate was concentrated under reduced pressure to afford the titlecompound (2.5 g, 63.4% yield) as a brown oil. LCMS (ESI) [M+H]⁺=241.2

Step 4: Benzyl3-((tert-butoxycarbonyl)amino)-5-cyclopropylpiperidine-1-carboxylate

To a solution of tert-butyl N-(5-cyclopropyl-3-piperidyl)carbamate (3.5g, 7.28 mmol) and triethylamine (4.0 g, 39.53 mmol) in tetrahydrofuran(40 mL) was added benzyl chloroformate (3.5 g, 20.52 mmol) and stirredat rt for 2 h. The resulting solution was diluted with water, extractedwith ethyl acetate, washed with brine, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica flashchromatography eluting with dichloromethane/methanol (99:1) to affordthe title compound (2.6 g, 66.7% yield) as brown oil. LCMS (ESI)[M+H]⁺=375.2.

Step 5: Benzyl 3-amino-5-cyclopropylpiperidine-1-carboxylate

To a solution of benzyl3-(tert-butoxycarbonylamino)-5-cyclopropyl-piperidine-1-carboxylate (2.7g, 5.05 mmol) in dichloromethane (10 mL) was added 4 M HCl in dioxane(15 mL) and stirred at rt for 2 h. The solvent was concentrated undervacuum. The crude product was purified by Prep-HPLC to afford the titlecompound (700 mg, 48% yield) as brown oil. LCMS (ESI): [M+H]⁺=275.2

Step 6: Benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a mixture of benzyl3-amino-5-cyclopropyl-piperidine-1-carboxylate hydrochloride (426 mg,1.37 mmol),1-(2-fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(1.5 g, 1.32 mmol), cesium fluoride (1200 mg, 7.9 mmol) andN,N-diisopropylethylamine (600 mg, 4.64 mmol) in dimethyl sulfoxide (12mL) was stirred at 85° C. for 1 h. The resulting solution was dilutedwith water, extracted with ethyl acetate, washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silicaflash chromatography eluting with ethyl acetate/petroleum ether (80:20).The crude product was further purified by Prep-HPLC and Chiral HPLC toafford four isomers. Isomer 1, isomer 2, isomer 3, isomer 4 wereassigned arbitrarily.

Benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 1) (48 mg, 4.7% yield) as a white solid. LCMS (ESI):[M+H]⁺=763.2.

Benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 2) (46 mg, 4.5% yield) as a white solid. LCMS (ESI):[M+H]⁺=763.2.

Benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 3) (200 mg, 19.7% yield) as a white solid. LCMS (ESI):[M+H]⁺=763.2.

Benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 4) (210 mg, 20.7% yield) as a white solid. LCMS (ESI):[M+H]⁺25=763.2.

Step 7:N-(4-((3-(2-((5-Cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 324

To a solution of benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-((2-fluorophenyl)methylsulfonylamino)phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 1 of step 6) (48 mg, 0.06 mmol) in dichloromethane (0.3 mL) andacetonitrile (0.30 mL) was added dimethyl sulfide (0.5 mL) and borontrifluoride etherate (0.5 mL) and stirred at rt for 2 h. The reactionwas quenched with sat. sodium bicarbonate. The resulting solution wasextracted with ethyl acetate, washed with brine, and concentrated. Theproduct was purified by Prep-HPLC to afford the title compound (24.9 mg,61.6% yield) as a white solid.

Step 8:N-(4-((3-(2-((5-Cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 325

To a solution of benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-((2-fluorophenyl)methylsulfonylamino)phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 2 of step 6) (46 mg, 0.06 mmol) in dichloromethane (0.3 mL) andacetonitrile (0.30 mL) was added dimethyl sulfide (0.5 mL) and borontrifluoride etherate (0.5 mL) and stirred at rt for 2 h. The reactionwas quenched with sat. sodium bicarbonate. The resulting solution wasextracted with ethyl acetate, washed with brine, and concentrated. Theproduct was purified by Prep-HPLC to afford the title compound (23.4 mg,61% yield) as a white solid.

Step 9:N-(4-((3-(2-((5-Cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 326

To a solution of benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-((2-fluorophenyl)methylsulfonylamino)phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 3 of step 6) (200 mg, 0.26 mmol) in dichloromethane (1.25 mL)and acetonitrile (1.25 mL) was added dimethyl sulfide (1.5 mL) and borontrifluoride etherate (1.5 mL) was added and stirred at rt for 2 h. Thereaction was quenched with sat. sodium bicarbonate. The resultingsolution was diluted with water, extracted with ethyl acetate, washedwith brine, and concentrated. The product was purified by Prep-HPLC toafford the title compound (104.8 mg, 63% yield) as a white solid.

Step 10:N-(4-((3-(2-((5-Cyclopropylpiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 327

To a solution of benzyl3-cyclopropyl-5-((4-(2-(2,3,5-trifluoro-4-((2-fluorophenyl)methylsulfonylamino)phenoxy)-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 4 of step 6) (210 mg, 0.27 mmol) in dichloromethane (1.25 mL)and acetonitrile (1.25 mL) was added dimethyl sulfide (1.5 mL) and borontrifluoride etherate (1.5 mL) was added and stirred at rt for 2 h. Thereaction was quenched with sat. sodium bicarbonate. The resultingsolution was diluted with water, extracted with ethyl acetate, washedwith brine, and concentrated. The product was purified by Prep-HPLC toafford the title compound (107.5 mg, 64.6% yield) as a white solid.

Example 1081-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 328 & Compound 329 & Compound 331

Step 1: 1-(tert-Butyl) 3-methyl5-(benzyloxy)piperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-methyl5-hydroxypiperidine-1,3-dicarboxylate (8.0 g, 31 mmol) inN,N-dimethylformamide (80 mL) was added sodium hydride (1.85 g, 46 mmol)at 0° C. and reacted for 0.5 h at rt. Then benzyl bromide (0.99 mL, 8.34mmol) was added and stirred at rt for 2 h. The reaction was quenchedwith sat ammonium chloride and extracted with ethyl acetate. The organiclayer was washed with brine (10 mL), dried over anhydrous sodium sulfateand concentrated under vacuum. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/petroleum ether (0-100%) to afford the title compound(8.2 g, 75.8% yield) as a colorless oil. LCMS (ESI): [M+H]⁺=350.1.

Step 2: tert-Butyl3-(benzyloxy)-5-(hydroxymethyl)piperidine-1-carboxylate

A solution of 1-tert-butyl 3-methyl5-benzyloxypiperidine-1,3-dicarboxylate (2.7 g, 7.7 mmol) and calciumchloride (1.59 g, 14 mmol) in tetrahydrofuran (60 mL) was stirred at 0°C. for 0.5 h. Then sodium borohydride (1.36 g, 36 mmol) was added andstirred at rt for 24 h. The reaction was quenched with ice water (50mL). The resulting solution was extracted with ethyl acetate and theorganic layers were combined. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica flash chromatography eluting with methanol/dichloromethane(0-5%) to afford the title compound (2.4 g, 96.6% yield) as a colorlessoil. LCMS (ESI): [M+H]⁺=322.2.

Step 3: tert-Butyl3-(benzyloxy)-5-(methoxymethyl)piperidine-1-carboxylate

Into a solution of tert-butyl3-benzyloxy-5-(hydroxymethyl)piperidine-1-carboxylate (2.5 g, 7.9 mmol)in tetrahydrofuran (25 mL) was added sodium hydride (450 mg, 11 mmol),the mixture was stirred at 0° C. for 0.5 h, then iodomethane (3.3 g, 23mmol) was added at the same temperature and stirred for 24 h at rt. Thereaction was quenched with sat. ammonium chloride (40 mL). The resultingsolution was extracted with ethyl acetate and the organic layers werecombined. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (0-40%) toafford the title compound (2.6 g, 99.7% yield) as colorless oil. LCMS(ESI): [M+H]⁺=336.1.

Step 4: tert-Butyl 3-hydroxy-5-(methoxymethyl)piperidine-1-carboxylate

Into a solution of tert-butyl3-benzyloxy-5-(methoxymethyl)piperidine-1-carboxylate (2.6 g, 7.8 mmol)in methyl alcohol (100 mL) was added 10% Pd/C (700 mg), the mixture wasstirred at rt for 2 h under hydrogen. The reaction was filtered out. Thesolvent was removed under vacuum to afford the title compound (1.9 g,99.9% yield) as brown oil. LCMS (ESI): [M+H]⁺=246.

Step 5: tert-Butyl3-(methoxymethyl)-5-((methylsulfonyl)oxy)piperidine-1-carboxylate

Into a solution of tert-butyl3-hydroxy-5-(methoxymethyl)piperidine-1-carboxylate (2.3 g, 9.4 mmol) indichloromethane (40 mL) was added triethylamine (3.8 g, 37 mmol) andmethanesulfonyl chloride (1.83 g, 16 mmol), the mixture was stirred at0° C. for 2 h. The reaction mixture was diluted with water (20 mL). Theresulting solution was extracted with dichloromethane and the organiclayers were combined. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum to afford the title compound (3.0g, 98.9% yield) as dark red oil. LCMS (ESI): [M+H]⁺=324.1.

Step 6: tert-Butyl 3-azido-5-(methoxymethyl)piperidine-1-carboxylate

Into a solution of tert-butyl3-(methoxymethyl)-5-methylsulfonyloxy-piperidine-1-carboxylate (3.0 g,9.3 mmol) in N,N-dimethylacetamide (70 mL) was added sodium azide (1.3g, 20 mmol), the mixture was stirred at 80° C. for 6 h under nitrogen.The reaction mixture was diluted with water and extracted with ethylacetate. The solvent was removed under vacuum to afford the titlecompound (2.5 g, 99.7% yield) as brown oil. LCMS (ESI): [M+H]⁺=271.2.

Step 7: tert-Butyl 3-amino-5-(methoxymethyl)piperidine-1-carboxylate

Into a solution of tert-butyl3-azido-5-(methoxymethyl)piperidine-1-carboxylate (2.5 g, 9.25 mmol) inmethyl alcohol (50 mL) was added 10% Pd/C (800 mg), the mixture wasstirred at rt for 1.5 h under hydrogen. The solids were filtered out.The solvent was removed under vacuum to afford the title compound (2.1g, 92.9% yield) as a brown oil. LCMS (ESI): [M+H]⁺=245.1.

Step 8: tert-Butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

Under nitrogen, a solution of tert-butyl3-amino-5-(methoxymethyl)piperidine-1-carboxylate (330 mg, 1.35 mmol)and1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl)oxy)phenyl)methanesulfonamide(500 mg, 0.9 mmol), caesium fluoride (415 mg, 2.73 mmol),N,N-diisopropylethylamine (350.0 mg, 2.71 mmol) in dimethyl sulfoxide (4mL) was stirred for 1 h at 80° C. The reaction mixture was diluted withwater and extracted with ethyl acetate. The solvent was removed undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (0-100%). The crude product wasfurther purified by Prep-HPLC and Chiral HPLC to afford four isomers.Isomer 1, isomer 2, isomer 3, isomer 4 were assigned arbitrarily.

tert-Butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 1) (60 mg, 9.2% yield). LCMS (ESI): [M+H]⁺=715.2.

tert-Butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 2) (60 mg, 9.2% yield). LCMS (ESI): [M+H]⁺=715.2.

tert-Butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 3) (68 mg, 10.5% yield). LCMS (ESI): [M+H]⁺=715.2.

tert-Butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 4) (80 mg, 12.3% yield). LCMS (ESI): [M+H]⁺=715.2.

Step 9:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 328

Into a solution of tert-butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 1) (60 mg, 0.08 mmol) in dichloromethane (2 mL) was added 4 MHCl in dioxane (1 mL), the mixture was stirred at rt for 2 h. Thereaction mixture was concentrated under vacuum. The residue was purifiedby Prep-HPLC to afford the title compound (21.7 mg, 42.1% yield) as awhite solid.

Step 10:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 329

A solution of tert-butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 2) (60 mg, 0.08 mmol) in dichloromethane (2 mL) was added 4 MHCl in 1,4-dioxane (1 mL), the mixture was stirred at rt for 2 h. Thereaction mixture was concentrated under vacuum. The residue was purifiedby Prep-HPLC to afford the title compound (25.1 mg, 48.6% yield) as awhite solid.

Step 11:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 330

A solution of tert-butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 3) (68 mg, 0.1 mmol) in dichloromethane (2 mL) was added 4 M HClin 1,4-dioxane (1 mL), the mixture was stirred at rt for 2 h. Thereaction mixture was concentrated under vacuum. The residue was purifiedby Prep-HPLC to afford the title compound (29.4 mg, 50.3% yield) as awhite solid.

Step 12:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(methoxymethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 331

A solution of tert-butyl3-(methoxymethyl)-5-((4-(2-(2,3,5-trifluoro-4-((phenylmethyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(isomer 4) (80 mg, 0.11 mmol) in dichloromethane (2 mL) was added 4 MHCl in 1,4-dioxane (1 mL), the mixture was stirred at rt for 2 h. Thereaction mixture was concentrated under vacuum. The residue was purifiedby Prep-HPLC to afford the title compound (36.3 mg, 52.8% yield) as awhite solid.

Example 109N-(3-Chloro-2,6-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 332

The title compound was prepared according to example 112. This resultedin the title compound (45.7 mg, 61.9% yield) as a yellow solid.

Example 1101-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 333 & Compound 334 & Compound 335 & Compound 336

Step 1: tert-Butyl3-benzyloxy-5-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxylate

To a mixture of 1-(tert-butyl) 3-methyl5-(benzyloxy)piperidine-1,3-dicarboxylate (3.0 g, 8.6 mmol) intetrahydrofuran (60 mL) was added 3 M methylmagnesium bromide intetrahydrofuran (9 mL, 27 mmol) at −78° C. and stirred for 2 h at thesame temperature. The reaction was quenched with sat ammonium chloride(40 mL). The resulting solution was extracted with ethyl acetate and theorganic layers were combined. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with ethylacetate/petroleum ether (0-40%) to afford the title compound (1.6 g,53.3% yield) as a colorless oil. LCMS (ESI): [M+H]⁺=350.3

Step 2: tert-Butyl3-(benzyloxy)-5-(2-fluoropropan-2-yl)piperidine-1-carboxylate

A mixture of tert-butyl3-benzyloxy-5-(l-hydroxy-1-methyl-ethyl)piperidine-1-carboxylate (2.7 g,7.7 mmol) in diethylaminosulfur trifluoride (12 mL, 7.7 mmol) wasstirred at rt for 1 h under nitrogen. The resulting solution was pouredinto sat. sodium carbonate at 0° C. The resulting solution was extractedwith ethyl acetate and washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica flash chromatographyeluting with ethyl acetate/petroleum ether (1/4) to afford the titlecompound (1.3 g 47.9% yield) as colorless oil. LCMS (ESI): [M+H]⁺=352.3

Step 3:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 333 & Compound 334 & Compound 335 & Compound 336

The title compound was prepared according to example 108.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 333 (21.1 mg, 51.4% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 334) (20.8 mg, 49.5% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 335) (20.9 mg, 61.9% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(2-fluoropropan-2-yl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride (Compound 336) (18.9 mg, 50.5% yield) as a white solid.

Example 111N-(4-((3-(2-((5-(1,1-Difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride (mixture of enantiomers) Compound 337 & Compound 338 &Compound 339

Step 1: 5-Benzyloxy-1-tert-butoxycarbonyl-piperidine-3-carboxylic acid

Into the solution of 1-(tert-butyl) 3-methyl5-(benzyoxy)piperidine-1,3-dicarboxylate (6.1 g, 17 mmol) intetrahydrofuran (30 mL), ethanol (30 mL) and water (10 mL) was addedlithium hydroxide monohydrate (5.4 g, 129 mmol). The mixture was stirredat rt for 4 h. The mixture was diluted with water and adjusted to pH=4with hydrochloric acid (0.5 M). The mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated under vacuum to afford the title compound (5.8 g, 99.1%yield) as a white solid. LCMS (ESI): [M+H−56]⁺=280.1.

Step 2: tert-Butyl3-benzyloxy-5-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

Into the solution of5-benzyloxy-1-tert-butoxycarbonyl-piperidine-3-carboxylic acid (6.5 g,19 mmol) in dichloromethane (150 mL) was added N,O-dimethylhydroxylaminehydrochloride (2.9 g, 29 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbocliimide hydrochloride (5.7 g, 29mmol), 4-hydroxybenzotriazole (4.0 g, 29 mmol) andN,N-diisopropylethylamine (13 mL, 81 mmol). The solution was stirred atrt for 16 h. The solution was diluted with water and extracted withdichloromethane. The solution was dried over sodium sulfate andconcentrated under vacuum. The residue was purified by silica flashchromatography eluting with ethyl acetate/petroleum ether (10%-50%) toafford the title compound (5.5 g, 75% yield) as colorless oil. LCMS(ESI): [M+H]⁺=379.1.

Step 3: tert-Butyl 3-acetyl-5-benzyloxy-piperidine-1-carboxylate

Under nitrogen, into the solution of tert-butyl3-benzyloxy-5-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.5g, 46 mmol) in tetrahydrofuran (12 OmL) was added 3 Mmethylmagnesiumbromide in tetrahydrofuran (50 mL, 150 mmol) at −60° C.The solution was stirred at rt for 3 h. The reaction was quenched withsat. ammonium chloride and extracted with ethyl acetate. The solutionwas dried over sodium sulfate and concentrated under vacuum. The residuewas purified by silica flash chromatography eluting withdichloromethane/petroleum ether (10%-80%) to afford the title compound(14.2 g, 92.1% yield) as colorless oil. LCMS (ESI): [M+H+22]⁺=356.1

Step 4: tert-Butyl3-benzyloxy-5-(1,1-difluoroethyl)piperidine-1-carboxylate

A solution of tert-butyl 3-acetyl-5-benzyloxy-piperidine-1-carboxylate(2.5 g, 7.5 mmol) in bis(2-methoxyethyl)aminosulfur trifluoride (15 mL,82 mmol) was stirred at 50° C. for 3 h. The solution was diluted withdichloromethane and quenched with sat. sodium bicarbonate. The mixturewas extracted with dichloromethane. The solution was dried over sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(0%-40%) to afford the title compound (1.2 g, 45% yield) as colorlessoil. LCMS (ESI): [M+H−56]⁺=300.1.

Step 5:N-(4-((3-(2-((5-(1,1-Difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride (mixture of enantiomers) Compound 337 & Compound 338 &Compound 339

The title compound was prepared according to example 108.

N-(4-((3-(2-((5-(1,1-Difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamidehydrochloride (Compound 337, mixture of enantiomers) (17.9 mg, 98%yield) as a white solid and as HCl salt.

N-(4-((3-(2-((5-(1,l-Difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(Compound 338) (92.2 mg, 23.7% yield) as a light brown solid, (rt=3.05min, SFC CHIRALPAK AD-3 3*100 mm, 3 um, EtOH(0.1% DEA), 10% to 50% in4.0 min, hold 2.0 min at 50%, 2.0 mL/min). Compound 338 & Compound 339are enantiomers.

N-(4-((3-(2-((5-(1,l-Difluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-1-phenylmethanesulfonamide(Compound 339) (97.5 mg, 25.1% yield) as a light brown solid, (rt=3.274min, SFC CHIRALPAK AD-3 3*100 mm, 3 um, EtOH(0.1% DEA), 10% to 50% in4.0 min, hold 2.0 min at 50%, 2.0 mL/min). Compound 338 & Compound 339are enantiomers.

Example 112N-(5-Chloro-2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 340

Step 1: 2-(Benzyloxy)-5-bromo-1-chloro-3,4-difluorobenzene

A solution of 4-bromo-6-chloro-2,3-difluoro-phenol (840 mg, 3.5 mmol)and sodium hydride (278 mg, 7.0 mmol) in N,N-dimethylacetamide (5 mL)was stirred at 0° C. for 0.5 h. Then benzyl bromide (1781 mg, 10 mmol)was added and stirred at rt for 16 h. The reaction was quenched with satammonium chloride and extracted with ethyl acetate and washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (1%) to afford the title compound(810 mg, 70.4% yield) as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ7.65-7.51 (m, 1H), 7.50-7.37 (m, 5H), 5.28-5.17 (m, 2H).

Step 2:N-(4-(benzyloxy)-5-chloro-2,3-difluorophenyl)-1,1-diphenylmethanimine

Under nitrogen, a solution of4-benzyloxy-1-bromo-5-chloro-2,3-difluoro-benzene (600 mg, 1.8 mmol),benzophenone imine (488 mg, 2.7 mmol),tris(dibenzylideneacetone)dipalladium(0) (163 mg, 0.18 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (208 mg, 0.36 mmol),cesium carbonate (1164 mg, 3.6 mmol) in 1,4-dioxane (4 mL) was stirredfor 2 h at 80° C. The reaction was quenched with water and extractedwith ethyl acetate and washed with brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(20%) to afford the title compound (700 mg, 89.7% yield) as yellow oil.LCMS (ESI): [M+H]⁺=434.2.

Step 3: 4-(Benzyloxy)-5-chloro-2,3-difluoroaniline

Into a solution ofN-(4-benzyloxy-5-chloro-2,3-difluoro-phenyl)-1,1-diphenyl-methanimine(700 mg, 1.6 mmol) in water (3 mL) was added tetrahydrofuran (10 mL) andacetic acid (10 mL), the mixture was stirred at rt for 16 h. Thereaction was extracted with ethyl acetate and washed with brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by silica flash chromatography eluting with ethylacetate/petroleum ether (1/1) to afford the title compound (200 mg, 46%yield) as a light yellow solid. LCMS (ESI): [M+H]⁺=270.2.

Step 4:N-(4-(Benzyloxy)-5-chloro-2,3-difluorophenyl)-1-(2-fluorophenyl)methanesulfonamide

A solution of (2-fluorophenyl)methanesulfonyl chloride (233 mg, 1.12mmol) and 4-benzyloxy-5-chloro-2,3-difluoro-aniline (200 mg, 0.74 mmol)in pyridine (1 mL) was stirred at rt for 1 h. The reaction was quenchedwith water and extracted with ethyl acetate and washed with brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by silica flash chromatography eluting with ethylacetate/petroleum ether (0-50%) to afford the title compound (254 mg,77.5% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=442.2.

Step 5:N-(5-Chloro-2,3-difluoro-4-hydroxyphenyl)-1-(2-fluorophenyl)methanesulfonamide

Into a solution ofN-(4-benzyloxy-5-chloro-2,3-difluoro-phenyl)-1-(2-fluorophenyl)methanesulfonamide(154 mg, 0.35 mmol) in methyl alcohol (20 mL) was added 10% Pd/C (50mg), the mixture was stirred at rt for 1.5 h under hydrogen. The solidswere filtered out. The solvent was removed. The residue was purified bysilica flash chromatography eluting with ethyl acetate/petroleum ether(0-60%) to afford the title compound (120 mg, 99% yield) as a whitesolid. LCMS (ESI): [M−H]⁻=350.1.

Step 6: tert-Butyl(3S,5S)-3-((4-(2-(6-chloro-2,3-difluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate

Under nitrogen, a solution of tert-butyl(3S,5S)-3-fluoro-5-((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(120 mg, 0.31 mmol),N-(5-chloro-2,3-difluoro-4-hydroxy-phenyl)-1-(2-fluorophenyl)methanesulfonamide(132 mg, 0.38 mmol) and cesium carbonate (498 mg, 1.53 mmol) in dimethylsulfoxide (2 mL) was stirred at 100° C. for 1.5 h. The reaction wasquenched with water and extracted with ethyl acetate and washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica flash chromatography elutingwith ethyl acetate/petroleum ether (0-80%) to afford the title compound(145 mg, 65.4% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=723.1.

Step 7:N-(5-Chloro-2,3-difluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-fluorophenyl)methanesulfonamideCompound 340

Into a solution of tert-butyl(3S,5S)-3-((4-(2-(6-chloro-2,3-difluoro-4-(((2-fluorophenyl)methyl)sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-fluoropiperidine-1-carboxylate(130 mg, 0.18 mmol) in dichloromethane (2 mL) was added 4 M HCl in1,4-dioxane (1 mL, 4 mmol), the mixture was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum. The residue was purified byPrep-HPLC to afford the title compound (45.4 mg, 40.5% yield) as a whitesolid.

Example 1131-(4-Fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 341

The title compound was prepared according to example 38. This providesthe title compound (39.9 mg, 17.7% yield) as a white solid and as HClsalt.

Example 1141-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 342 Compound 343 Compound 344 Compound 345 &1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 346 Compound 347 Compound 348 Compound 349

Step 1: tert-Butyl3-benzyloxy-5-(l-hydroxyethyl)piperidine-1-carboxylate

To a solution of tert-butyl3-acetyl-5-benzyloxy-piperidine-1-carboxylate (3.2 g, 9.6 mmol) inmethyl alcohol (80 mL) was added sodium borohydride (768 mg, 20 mmol).The solution was stirred for 20 min at rt. The reaction was quenchedwith water and extracted with dichloromethane. The combined organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to afford the title compound (3.2 g, 99.4% yield) as a lightyellow oil. LCMS (ESI): [M+1-56]⁺=280.1

Step 2: tert-Butyl 3-benzyloxy-5-(1-fluoroethyl)piperidine-1-carboxylate

A solution of tert-butyl3-benzyloxy-5-(1-hydroxyethyl)piperidine-1-carboxylate (3.2 g, 9.5 mmol)in diethylaminosulfur trifluoride (21 mL) was stirred at rt for 2 h. thesolution was diluted with dichloromethane. The above solution was slowlyadded into ice/water and extracted with dichloromethane. The solutionwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by silica flash chromatography eluting withdichloromethane/petroleum ether (30%-90%) to afford the title compound(1.3 g, 40.4% yield) as an orange oil.

Step 3:1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 342 Compound 343 Compound 344 Compound 345 &1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 346 Compound 347 Compound 348 Compound 349

The title compound was prepared according to example 108.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 342 (47.5 mg, 73.4% yield) as a white solid andas HCl salt.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 346 (3.6 mg, 34.9% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 343 (19.8 mg, 62.1% yield) as a white solid asHCl salt.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 347 (13.9 mg, 27.9% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 344 (20.2 mg, 88.7% yield) as a white solid asHCl salt.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 345 (22.9 mg, 43.3% yield) as a white solid asHCl salt.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 348 (48.9 mg, 59.8% yield) as a white solid.

1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-((5-(1-fluoroethyl)piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamidehydrochloride Compound 349 (1.2 mg, 9.4% yield) as a white solid as HClsalt.

Example 115N-(2,3,6-Trifluoro-4-((3-(2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamideCompound 350

Step 1:N-(2,3,6-Trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide

To a mixture of2,3,6-trifluoro-4-((3-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl)oxy)aniline(0.25 g, 0.69 mmol) in 1,8-diazabicyclo[5.4.0]undec-7-ene (2 mL) wasadded cyclohexanesulfonylchloride (0.38 g, 2.1 mmol), the mixture wasstirred for 48 h at rt. The resulting solution was diluted with waterand extracted with ethyl acetate, the organic layers was washed withbrine and dried over sodium sulfate and concentrated. The residue waspurified by silica flash chromatography eluting with ethylacetate/petroleum ether (2:1) to afford the title compound (130 mg,37.1% yield) as a brown solid. LCMS (ESI): [M+H]⁺=511.3.

Step 2:N-(2,3,6-trifluoro-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide

To a mixture ofN-(2,3,6-trifluoro-4-((3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide(0.11 g, 0.22 mmol) in dichloromethane (3 mL) was added3-chloroperoxybenzoic acid (0.11 g, 0.65 mmol), the mixture was stirredfor 1 h at rt. The reaction was quenched with sat. sodium bisulfite. Theresulting solution was extracted with dichloromethane and dried oversodium sulfate and concentrated. The crude would be directly used in thenext step without purification. LCMS (ESI): [M+H]⁺=543.3

Step 3:N-(2,3,6-Trifluoro-4-((3-(2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamideCompound 350

A mixture ofN-(2,3,6-trifluoro-4-((3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamide(0.1 g, 0.18 mmol),N⁴-(2-methoxyethyl)-N⁴-methyl-cyclohexane-1,4-diamine (0.03 g, 0.18mmol), caesium fluoride (0.08 g, 0.55 mmol) andN,N-diisopropylethylamine (71 mg, 0.55 mmol) in dimethyl sulfoxide (3mL) was stirred at 85° C. for 2 h under nitrogen. The crude product wasdirectly purified by reverse phase and Prep-HPLC to afford the titlecompound (38.9 mg, 32.5% yield) as a white solid.

Example 1161-(2,4-Difluorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 351

The title compound was prepared according to example 40. This resultedin the title compound (25 mg, 38% yield) as a white solid.

Example 1171-(2-Chlorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 352

The title compound was prepared according to example 40. This resultedin the title compound (52 mg, 79% yield) as a white solid.

Example 1181-(3-Chlorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 353

The title compound was prepared according to example 40. This resultedin the title compound (12 mg, 18% yield) as a white solid.

Example 1191-(4-Chlorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 354

The title compound was prepared according to example 40. This resultedin the title compound (37 mg, 56% yield) as a white solid.

Example 1201-(2-Fluorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 355

The title compound was prepared according to example 40. This resultedin the title compound (20 mg, 31% yield) as a white solid.

Example 1211-(2-Pyridyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 356 Step 1: Benzyl(3S,5S)-3-fluoro-5-[[4-[2-[2,3,5-trifluoro-4-(2-pyridylmethylsulfonylamino)phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

To benzyl(3S,5S)-3-[[4-[2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate(40 mg, 0.07 mmol) in DCM (0.1 M) was added trimethylamine (0.28 mmol,40 μL). The reaction was quenched after 1 min with a saturated sodiumbicarbonate solution. FastworX-S resin (˜300 mg) was added and theremaining DCM was removed in vacuo. The reaction mixture was filtered tocollect the resin directly into a solid loading cartridge. Normal phasechromatography (ISCO) was run using 0-20% MeOH/DCM gradient and 54 mg ofthe title compound (˜quantitative yield) was isolated as a mixture ofmonomer and dimer. LCMS (ESI): [M+H]⁺=724/879.

Step 2:1-(2-Pyridyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 356

The title compound was prepared according to example 40 step 2. Thisresulted in the title compound (2.4 mg, 5.4% yield) as a white solid.

Example 1221-(2-Cyano-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 357

The title compound was prepared according to example 40. This resultedin the title compound (13 mg, 20% yield) as a white solid.

Example 123

1-(2-Cyano-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-((3-[2-[[(3S,5S)-5-fluoro-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 358

Example 1241-(2-Cyano-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 359

The title compound was prepared according to example 40. This resultedin the title compound (2 mg, 4% yield) as a white solid.

Example 1253-Fluoro-4-[[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]sulfamoylmethyl]benzamideCompound 360 Step 1: tert-Butyl(3S,5S)-3-[[4-[2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

2,3,6-Trifluoro-4-[[3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]oxy]aniline(750 mg, 1.89 mmol) in dimethyl sulfoxide (9.5 mL) was added tert-butyl(3S,5S)-3-amino-5-fluoropiperidine-1-carboxylate (2.2 mmol),N,N-diisopropylethylamine (1.1.mL, 6.4 mmol) and cesium fluoride (5.7mmol). The mixture was stirred at 90° C. for 16 h. The mixture wasdiluted with water (50 mL) and ethyl acetate (50 mL). The mixture wasextracted with ethyl acetate (3×50 mL) and the organic layer wascombined. The solution was washed with water (3×10 mL), brine (20 mL),dried over sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with isoproyl acetate in heptanes(0-100%) to the title compound (550 mg, 54% yield) as a white solid.LCMS (ESI): [M+H]⁺=536.1.

Step 2: tert-Butyl(3S,5S)-3-[[4-[2-[4-[(4-cyano-2-fluoro-phenyl)methylsulfonylamino]-2,3,5-trifluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

To tert-butyl(3S,5S)-3-[[4-[2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate(50 mg, 0.09 mmol) in DCM (0.25 M) was added pyridine (38 μL, 0.47 mmol)followed by (4-cyano-2-fluorophenyl)methanesulfonyl chloride (27 mg,0.11 mmol). The reaction was stirred at room temperature for 2 hoursthen quenched with saturated sodium bicarbonate solution (10 mL) andextracted with DCM (10 mL). The crude organic layers was dried withmagnesium sulfate, filtered, dried and taken into the next step withoutfurther purification to afford the title compound in quantitative yield.LCMS (ESI): [M+H]⁺=732.1

Step 3:3-Fluoro-4-[[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]sulfamoylmethyl]benzamideCompound 360

To tert-butyl(3S,5S)-3-[[4-[2-[4-[(4-cyano-2-fluoro-phenyl)methylsulfonylamino]-2,3,5-trifluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate(68 mg, 0.09 mmol) in MeOH (2 mL) was added hydrochloric acid (4.0mol/L) in dioxane (0.9 mmol, 0.24 mL). The reaction was stirred for 6hours at room temperature and then concentrated to dryness and submittedfor reverse phase HPLC purification to afford the title compound (31 mg,47% yield).

Example 1263-Fluoro-4-[[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]sulfamoylmethyl]benzamideCompound 361

The title compound was prepared according to example 40. This resultedin the title compound (23 mg, 34% yield) as a white solid.

Example 1273-Fluoro-4-[[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]sulfamoylmethyl]benzamideCompound 362

The title compound was prepared according to example 40. This resultedin the title compound (11 mg, 16% yield) as a white solid.

Example 1281-(2,6-Difluorophenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 363

The title compound was prepared according to example 40. This resultedin the title compound (12 mg, 19% yield) as a white solid.

Example 1291-(4-Chloro-2-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 364 Step 1: Benzyl(3S,5S)-3-[[4-[2-[4-[(4-chloro-2-fluoro-phenyl)methylsulfonylamino]-2,3,5-trifluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

To benzyl(3S,5S)-3-[[4-[2-(4-amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate(100 mg, 0.18 mmol) in DCM (0.1 M) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mmol, 80 μL). The reaction wasstirred at 40° C. and quenched with saturated sodium bicarbonatesolution (˜20 mL). FastworX-S resin (˜400 mg) was added and theremaining DCM was removed in vacuo. The resin was filtered/collected andthe crude intermediate was eluted with DCM (˜5 mL). Alternatively, thisworkup can be done without FastworX-S resin using DCM to extract theaqueous layer (˜20 mL) to afford the title compound as a crudeintermediate (˜quantitative yield). If the sulfonylation reactionproduces mostly dimer, the dimer can be hydrolyzed to monomer usingNaHCO3 (3-5 eq) and heating crude intermediate in a mixture of 2:1acetone/water at 50° C. for 1-18 hours. LCMS (ESI): [M+H]⁺=775.0.

Step 2:1-(4-Chloro-2-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 364

To benzyl(3S,5S)-3-[[4-[2-[4-[(4-chloro-2-fluoro-phenyl)methylsulfonylamino]-2,3,5-trifluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylatein DCM (0.2 M) was added hydrobromic acid (33 wt % in acetic acid, 3equiv., 0.54 mmol). The reaction was stirred for 2 h at room temperatureand quenched with water or methanol (1 mL), concentrated to dryness andsubmitted for reverse phase purification to afford the title compound(31 mg, 28% yield).

Example 1301-(2-Chloro-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 365

The title compound was prepared according to example 129. This resultedin the title compound (18 mg, 27% yield) as a white solid.

Example 1311-(3-Chloro-4-fluoro-phenyl)-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-3-piperidyl]amino]pyrimidin-4-yl]-2-pyridyl]oxy]phenyl]methanesulfonamideCompound 366

The title compound was prepared according to example 129. This resultedin the title compound (8 mg, 10% yield) as a white solid.

Example 1321-(2-Chloro-6-fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 367

The title compound was prepared according to example 129. This resultedin the title compound (30 mg, 36% yield) as a white solid.

Example 133N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclohexanesulfonamideCompound 368™

The title compound was prepared according to example 129. This resultedin the title compound (19 mg, 35% yield) as a white solid.

Example 134N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)cyclopentanesulfonamideCompound 369

The title compound was prepared according to example 129. This resultedin the title compound (12 mg, 34% yield) as a white solid.

Example 135N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamideCompound 370

The title compound was prepared according to example 129. This resultedin the title compound (15 mg, 25% yield) as a white solid.

Example 1361-(4-(Difluoromethyl)phenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 371

The title compound was prepared according to example 129. This resultedin the title compound (11 mg, 19% yield) as a white solid.

Example 1371-(4-Fluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 372

The title compound was prepared according to example 129. This resultedin the title compound (4 mg, 7% yield) as a white solid.

Example 138N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)phenyl)methanesulfonamideCompound 373

The title compound was prepared according to example 129. This resultedin the title compound (17 mg, 27% yield) as a white solid.

Example 139N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(3-(trifluoromethyl)phenyl)methanesulfonamideCompound 374

The title compound was prepared according to example 129. This resultedin the title compound (24 mg, 28% yield) as a white solid.

Example 1401-p-Tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 375

The title compound was prepared according to example 129. This resultedin the title compound (10 mg, 29% yield) as a white solid.

Example 1411-(Bicyclo[2.2.1]heptan-1-yl)N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 376

The title compound was prepared according to example 129. This resultedin the title compound (27 mg, 32% yield) as a white solid.

Example 1421-(Bicyclo[2.2.2]octan-1-yl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 377

The title compound was prepared according to example 129. This resultedin the title compound (18 mg, 22% yield) as a white solid.

Example 1431-(2,5-Difluorophenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 378

The title compound was prepared according to example 129. This resultedin the title compound (7 mg, 13% yield) as a white solid.

Example 1441-(4-Cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 379 Step 1: tert-Butyl(3S)-3-[[4-[2-(4-bromo-2,3-difluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate(3 g, 8 mmol) in DMSO (32 mL) was added 4-bromo-2,3-difluorophenol (2.2g, 10 mmol), Cs₂CO₃ (5.2 g, 16.1 mmol) and the reaction was stirred for2 h at 90° C. The reaction was quenched with water (100 mL) andextracted with DCM (100 mL). The organic layer was dried over anhydrousmagnesium sulfate, concentrated and purified by ISCO (0-70%Heptanes/IprOAc) to afford the title compound (2.5 g, 55% yield). LCMS(ESI): [M+2H]⁺=565.0.

Step 2: tert-Butyl(3S)-3-[[4-[2-[4-[l-(4-cyanophenyl)ethylsulfonylamino]-2,3-difluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

A vial containing tert-butyl(3S)-3-[[4-[2-(4-bromo-2,3-difluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(50 mg, 0.09 mmol) and 1-(4-cyanophenyl)ethane-1-sulfonamide (29.5 mg,0.13 mmol) was purged with nitrogen whereupon tBuBrettPhos G3 (7.9 mg,0.009 mmol) and potassium carbonate (25 mg, 0.18 mmol) were added andthe vial was re-purged with nitrogen. Degassed 1,4-dioxane (0.1M, 0.9mL) was added via syringe and the reaction was heated to 80° C. for 18hours. The reaction mixture was cooled and then FastworX-S resin (˜200mg) was added and the remaining DCM was removed in vacuo. The resin wasfiltered/collected and the crude intermediate was eluted with DCM (˜5mL) to afford the title compound as a crude intermediate (˜quantitativeyield). LCMS (ESI): [M+H]⁺=692.1.

Step 3:1-(4-Cyanophenyl)-N-(2,3-difluoro-4-((3-(2-(((S)-piperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 379

To tert-butyl(3S)-3-[[4-[2-[4-[1-(4-cyanophenyl)ethylsulfonylamino]-2,3-difluoro-phenoxy]-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate(61 mg, 0.09 mmol) in MeOH (2 mL) was added hydrochloric acid (4.0mol/L) in dioxane (0.9 mmol, 0.24 mL). The reaction was stirred for 18hours at room temperature and then concentrated to dryness and submittedfor reverse phase HPLC purification to afford the title compound (19 mg,36% yield).

Example 145(S)—N-(2,3-Difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-methoxyphenyl)methanesulfonamideCompound 380

The title compound was prepared according to example 144. This resultedin the title compound (26 mg, 33% yield) as a white solid.

Example 146(S)—N-(2,3-Difluoro-4-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-9H-fluorene-9-sulfonamideCompound 381

The title compound was prepared according to example 144. This resultedin the title compound (8 mg, 31% yield) as a white solid.

Example 147N-(4-((3-(2-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-3,3,3-trifluoropropane-1-sulfonamideCompound 382 Step 1:N¹-[4-[2-(4-Amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]-N⁴,N⁴-dimethyl-cyclohexane-1,4-diamine

2,3,6-Trifluoro-4-[[3-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]oxy]anilinewas reacted with N¹,N¹-dimethylcyclohexane-1,4-diamine dihydrochloridesimilar as in example 125 step 1 to afford the title compound (180 mg,62%) as a mixture of cis/trans isomers.

Step 2:N-(4-((3-(2-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-2,3,6-trifluorophenyl)-3,3,3-trifluoropropane-1-sulfonamideCompound 382

N¹-[4-[2-(4-Amino-2,3,5-trifluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]-N⁴,N⁴-dimethyl-cyclohexane-1,4-diaminewas reacted with 3,3,3-trifluoropropane-1-sulfonyl chloride similar asin example 129 step 1 to afford the title compound (4 mg, 3% based ontheoretical yield of desired trans product).

Example 1481-m-Tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 383

The title compound was prepared according to example 129. This resultedin the title compound (7 mg, 9% yield) as a white solid.

Example 1491-(2-Fluoro-4-methylphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 384

The title compound was prepared according to example 129. This resultedin the title compound (22 mg, 24% yield) as a white solid.

Example 1501-(3-Methoxyphenyl)-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 385

The title compound was prepared according to example 129. This resultedin the title compound (18 mg, 20% yield) as a white solid.

Example 1511-o-Tolyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)methanesulfonamideCompound 386

The title compound was prepared according to example 129. This resultedin the title compound (14 mg, 18% yield) as a white solid.

Example 153N-(2,3,6-Trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyridin-3-yl)methanesulfonamideCompound 389

The title compound was prepared according to example 129. This resultedin the title compound (41 mg, 55% yield) as a white solid.

Example 154(*S)-1-Phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 387 &(*R)-1-phenyl-N-(2,3,6-trifluoro-4-((3-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)ethane-1-sulfonamideCompound 388. *=arbitrarily assigned)

The title compounds were prepared according to example 99. This resultedin the title compounds (Compound 387; 21 mg, 54% yield and Compound 388;28 mg, 71% yield) as white solids.

Biological Examples

-   -   Exemplary compounds of Formula (I) were tested to assess        compound inhibition of IRE1 inbinding assays and functional        assays.

Example B1: IRE1α TR-FRET Competition Binding Assay

To determine the affinity of compound binding to the kinase domain ofIRE1 alpha, a Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) competition assay was used. A His-tagged IRE1 alpha kinasedead construct containing the kinase and RNase domains (KR, AAG547-L977, D688N) was expressed in Sf9 insect cells. The purifiedprotein (final concentration 0.006 μM micromolar) was pre-incubated withanti-His Europium labeled antibody (Life Technologies PV5596, finalconcentration 0.002 μM micromolar) for one hour at 4° C. in 1X TR-FRETAssay Buffer (50 mM HEPES, pH 7.5.10 mM MgCl₂,0.083 mM Brij 35, 1 mMDTT, and 0.1% bovine gamma globulin) prior to addition to testcompounds. A fluorescent labeled probe based on an ATP competitiveinhibitor (Kinase Tracer 236, Life Technologies PV5592) is added to afinal concentration of 0.1 μM (micromolar). Reactions were carried outfor one hour at room temperature in a final volume of 20 μL (microliter)in 384 well white ProxiPlates (Perkin Elmer 6008289). Binding of thetracer to the IRE1 protein alpha was detected in an Envision instrument(PerkinElmer) equipped with a TRF laser option and a LANCE/DelfiaDual/Bias D400/D630 mirror (Ex 347 nm, 1^(st) Em 665 nm, 2^(nd) Em 615nm).

-   -   Exemplary compounds in Table A1 were tested in the IRE1α binding        assays. The IC₅₀ values determined are listed in Table B1.

TABLE B1 Compound No. IRE1α TR-FRET IC₅₀ (μM) 101 0.013 102 0.010 1030.030 104 0.0059 105 0.027 106 0.0057 107 0.0052 108 0.0034 109 0.026110 0.0097 111 0.0044 112 0.0046 113 0.011 114 0.0073 115 0.03 116 0.023117 0.021 118 0.047 119 0.013 120 0.11 121 0.026 122 0.02 123 0.05 1240.21 125 0.027 126 0.28 127 0.37 128 0.011 129 0.23 130 0.17 131 0.059132 0.032 133 0.12 134 0.021 135 0.041 136 0.20 137 0.0074 138 0.015 1390.046 140 0.026 141 0.017 142 0.016 143 0.034 144 0.37 145 0.0078 1460.0040 147 0.21 148 0.0065 149 0.0087 150 0.30 151 0.084 152 0.0039 1530.0038 154 0.0038 155 0.0045 156 0.0046 157 0.029 158 0.0051 159 0.011160 0.0054 161 0.0042 162 0.0069 163 0.0066 164 0.0040 165 0.0027 1660.0035 167 0.017 168 0.067 169 0.0041 170 0.011 171 0.18 172 0.042 1730.0083 174 0.0031 175 0.0052 176 0.0025 177 0.0049 178 0.0035 179 0.0043180 0.038 181 0.036 182 0.0095 183 0.0085 184 0.057 185 0.0094 186 0.020187 0.0029 188 0.011 189 0.0050 190 0.0047 191 0.0043 192 0.0097 1930.033 194 0.0040 195 0.0046 196 0.0025 197 0.49 198 1.30 199 0.11 2000.53 201 0.21 202 0.0044 203 0.0033 204 0.0041 205 0.0044 206 0.0082 2070.0074 208 0.011 209 0.0075 210 0.023 211 0.033 212 0.025 213 0.0059 2140.044 215 0.011 216 0.013 217 0.016 218 0.016 219 0.053 220 0.019 2210.38 222 0.24 223 0.026 224 0.04 225 0.0061 226 0.018 227 0.0048 2280.0092 229 0.0064 230 0.014 231 0.0072 232 0.015 233 0.009 234 0.007 2350.004 236 0.009 237 0.0084 238 0.014 248 0.045 249 0.16 250 0.00490 2510.0028 252 0.014 253 0.0019 254 0.00062 255 0.23 256 0.001 257 0.024 2580.0052 259 0.002 260 0.0026 261 0.0035 262 0.00025 263 0.0015 264 0.0016265 0.0014 266 0.0086 267 0.0022 268 0.0011 269 0.0011 270 0.00054 2710.0036 272 0.00015 273 0.41 274 0.4 275 0.00023 276 0.18 277 0.027 2780.00078 279 0.00023 280 0.00031 281 0.00034 282 0.00027 283 0.00041 2840.00015 285 0.0089 286 0.26 287 0.0015 288 0.0011 290 0.0004 291 0.00028292 0.00033 293 0.00041 294 0.00059 295 0.041 296 0.014 297 0.00028 2980.0018 299 0.00038 300 0.0087 301 0.00036 302 0.00044 303 0.035 3040.00023 305 0.00021 306 0.043 307 0.00031 308 0.083 309 0.0011 3100.00032 311 0.00029 312 0.00014 313 0.0012 314 0.00024 315 0.00023 3160.00035 317 0.14 318 0.0003 319 0.00048 320 0.035 321 0.00065 3220.00042 323 0.00033 324 0.0004 325 0.022 326 0.00061 327 0.00026 3280.011 329 0.012 330 0.087 331 0.00082 332 0.056 333 0.00019 334 0.0098335 0.33 336 0.00042 337 0.0089 338 0.0026 339 0.00024 340 0.0075 3410.0005 342 0.00016 343 0.00078 344 0.019 345 0.00017 346 0.072 347 0.049348 0.0002 349 0.21 350 0.00042 351 0.00091 352 0.0002 353 0.0003 3540.0002 355 0.0002 356 0.0002 357 0.001 358 0.0003 359 0.0003 360 0.0008361 0.0003 362 0.0002 363 0.0002 364 0.0003 365 0.0007 366 0.0002 3670.0002 368 0.0002 369 0.0012 370 0.002 371 0.0003 372 0.0002 373 0.0003374 0.0002 375 0.0004 376 0.0002 377 0.0008 378 0.0011 379 0.0003 3800.0009 381 0.001 382 0.002 383 0.0007 384 0.0003 385 0.0002 386 0.0003387 0.0002 388 0.0008 389 0.0003

Example B2: IRE1 alpha RNase Activity Assay

Inhibitors of the RNase activity of IRE1α were assessed by Fluorescence(Forster) resonance energy transfer (FRET) using a mini-XBP-1 stem-loopRNA as a substrate for the IRE1α RNase activity. A 5′-Carboxyfluorescein (FAM)- and 3′-Black Hole Quencher (BHQ)-labeled XBP1 singlestem-loop mini-substrate oligonucleotide, TAQMAN® (Roche MolecularSystems) probe (Kutyavin et al (2000) Nucleic Acids Research,28(2):655-661) is cleaved by IRE1α. When the oligonucleotide is intact,the fluorescence signal is quenched by BHQ. Upon cleavage, thefluorescence is no longer quenched and can be quantified.

An IRE1 alpha construct corresponding to the linker, kinase and RNasedomains (LKR, AA Q470-L977) was expressed in Sf9 insect cells. Allreagent preparation and procedures are done under RNase free conditions.Test compounds and purified enzyme were combined in RNase Assay Buffer(20 mM HEPES, pH 7.5, 50 mM KAc, 1 mM MgAc, 1 mM DTT, and 0.05% TritonX-100) in a 384 well white ProxiPlate (Perkin Elmer 6008289). Uponaddition of the RNA substrate (final assay volume 20 μL, microliter),the plates were placed into a Flexstation 3 instrument (MolecularDevices) for kinetic fluorescence reading at 2 minute intervals (Ex 485,Em 535). The velocity of the reaction, using the first 50 minutes, wasused to calculate the RNase activity and inhibition of test compounds.

Exemplary compounds Table A1 had activity in the IRE1α RNase activityassay with an IC₅₀ of less than 10 μmol (micromolar).

Example B2: IRE1 Alpha Ribonuclease Luciferase Reporter Assay

HEK293 cells expressing a pBABE.puro HA-2xXBPl delta DBD fireflyluciferase reporter (Mendez etal., (2015) “Endoplasmic reticulumstress-independent activation of unfolded protein response kinases by asmall molecule ATP-mimic”, eLife; 4:e05434) were cultured in DMEM highglucose media containing L-glutamine, 10% fetal bovine serum, 100units/mL of penicillin and 100 μg/mL (microgram per milliliter) ofstreptomycin, plus 2 μg/ml puromycin to maintain selective pressure.Upon stimulation of IRE1 and activation of the endogenous RNaseactivity, a 26 nt intron is removed from XBP1 resulting in a frame shiftallowing the transcription of the luciferase.

Cells were seeded without puromycin at 10,000/well in 384 well clearbottom white tissue culture plates (Corning 3707), 25 μL volume. Thefollowing morning, test compounds were added and incubated for one hourat 37° C. prior to stimulation of the cells with thapsigargin at 50 μM(micromolar) final concentration for an additional 5 hours. Afterequilibration to room temperature, 25 μL (microliters) of One-Glo®luciferase detection reagent (Promega cat #E6120) was added, platessealed and shaken for 5 minutes to lyse cells, then luciferasequantified by luminescence detection using an Envision instrument(PerkinElmer).

Exemplary compound in Table A1 had activity in the XBP1s-LUC reporterassay with IC₅₀ of less than 10 μmol (micromolar).

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, “a polypeptide” is understood to representone or more polypeptides. As such, the terms “a” (or “an”), “one ormore,” and “at least one” can be used interchangeably herein.

All technical and scientific terms used herein have the same meaning.Efforts have been made to ensure accuracy with respect to numbers used(e.g. amounts, temperature, etc.) but some experimental errors anddeviations should be accounted for.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise. It is understood that embodimentsdescribed herein include “consisting of” and/or “consisting essentiallyof” embodiments.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±50%, in some embodiments±20%, in some embodiments ±10%, in some embodiments ±5%, in someembodiments ±1%, in some embodiments ±0.5%, and in some embodiments±0.1% from the specified amount, as such variations are appropriate toperform the disclosed methods or employ the disclosed compositions.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of the range and any other stated or intervening value in thatstated range, is encompassed herein. The upper and lower limits of thesesmall ranges which can independently be included in the smaller rangersis also encompassed herein, subject to any specifically excluded limitin the stated range. Where the stated range includes one or both of thelimits, ranges excluding either or both of those included limits arealso included herein.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R⁰ is hydrogenor fluoro; R¹ is C₃₋₁₂ cycloalkyl, 3- to 14-membered heterocyclyl, 5- to14-membered heteroaryl, —(C₁₋₆ alkylene)-(C₃-C₁₂ cycloalkyl), or —(C₁₋₆alkylene)-(3- to 14-membered heterocyclyl), —(C₁₋₆ alkylene)-OR^(1c), or—(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂ cycloalkyl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C₁₋₆alkylene of R¹ are independently optionally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰; each R^(1a), R^(1b)and R^(1c) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 14-memberedheteroaryl and 3- to 12-membered heterocyclyl of R^(1a) and R^(1b) areoptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰; R^(2A) and R²⁸ are independently hydrogen, halogen,cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), or—O(C₁₋₆ haloalkyl); R³ is hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, —O(C₁₋₆ alkyl), or —O(C₁₋₆ haloalkyl); R⁴and R⁵ are independently hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl, 3- to14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR^(7A),—NR^(8A)R^(8B), —NR⁸C(O)R⁷, —NR⁸C(O)OR^(7A), —NR⁸C(O)NR^(8A)R^(8B),—NR⁸SO₂R⁹, —NR⁸SO₂NR^(8A)R^(8B), —NR⁸S(O)(═NR^(8C))R⁹, —C(O)N(R⁸)SO₂R⁹,C(O)R⁷, —C(O)OR^(7A), —SO₂R⁹, —NR⁸S(O)(═NR^(8C))R⁹, or—SO₂NR^(8A)R^(8B); wherein the C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₂₀ aryl,3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl of R⁴and R⁵ are optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰; n is 0, 1, 2, or 3; each R⁶ isindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, —O(C₁₋₆ alkyl), —O(C₁₋₆ haloalkyl), —SO₂(C₁₋₆ alkyl) or—SO₂(C₁₋₆ haloalkyl); each R⁷ is independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, 5- to 14-membered heteroaryl, or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, 5- to 14-membered heteroaryl and 3- to 12-memberedheterocyclyl of R⁷ and R^(7A) are optionally substituted with 1, 2, 3, 4or 5 substituents independently selected from R¹⁰; each R^(7A) isindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to14-membered heteroaryl and 3- to 12-membered heterocyclyl of R⁷ andR^(7A) are optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰; each R⁸ is independently hydrogen orC₁-C₆ alkyl; each R^(8A) is independently hydrogen or C₁-C₆ alkyl; eachR^(8B) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, and 3- to12-membered heterocyclyl of R^(8B) are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰; each R^(8C) isindependently hydrogen or C₁-C₆ alkyl; each R⁹ is independently C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 14-memberedheteroaryl and 3- to 12-membered heterocyclyl; wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland 3- to 12-membered heterocyclyl are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰; each R¹⁰ isindependently oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 3- to 12-memberedheterocyclyl, halogen, cyano, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(c)R^(d),—OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —SR^(b), —S(O)R^(e),—S(O)₂R^(e), —S(O)(═NH)R^(e), —S(O)₂NR^(c)R^(d), —NR^(c)R^(d),—N(R^(f))C(O)R^(a), —N(R^(f))C(O)OR^(b), —N(R^(f))C(O)NR^(c)R^(d),—N(R^(f))S(O)₂R^(e), —N(R^(f))S(O)₂NR^(c)R^(d), —P(O)R^(g)R^(h) or—SiR^(i)R^(j)R^(k); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and 3- to14-membered heterocyclyl of R¹⁰ are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹; each R^(a) isindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3- to12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 12-membered heterocyclyl of R^(a) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹¹; eachR^(b) is independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl and 3- to 12-membered heterocyclyl of R^(b) are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹; each R^(c) and R^(d) is independently hydrogen, C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 12-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and 3- to 12-memberedheterocyclyl of R^(c) and R^(d) are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹; or R^(c) andR^(d) are taken together with the nitrogen atom to which they areattached to form a 4- to 12-membered heterocyclyl optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹¹; eachR^(e) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 12-membered heterocyclyl of R^(e) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹; each R^(f) is independently hydrogen or C₁₋₆ alkyl; each R^(g) andR^(h) is independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C₁₋₆alkyl; wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 12-membered heterocyclyl of R^(g) andR^(h) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹; or R^(g) and R^(h) are taken togetherwith the phosphorus atom to which they are attached to form a 4- to12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹; each R^(i), R^(j) andR^(k) is independently C₁₋₆ alkyl; each R¹¹ is independently oxo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano,—C(O)R^(a1), —C(O)OR^(b1), —C(O)NR^(c1)R^(d1), —OR^(b1), —OC(O)R^(a1),—OC(O)NR^(c1)R^(d1), —SR^(b1), —S(O)R^(e1), —S(O)₂R^(e1),—S(O)₂NR^(c1)R^(d1), —NR^(c1)R^(d1), —N(R^(f1))C(O)R^(a1),—N(R^(f1))C(O)OR^(b1), —N(R^(f1))C(O)NR^(c1)R^(d1),—N(R^(f1))S(O)₂R^(e1), —N(R^(f1))S(O)₂NR^(c1)R^(d1), —P(O)R^(g1)R^(h1),or —SiR^(i1)R^(j1)R^(k1); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, 5- to 14-membered heteroaryl and3- to 14-membered heterocyclyl of R¹¹ are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²; eachR^(a1) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or 3-to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and3- to 8-membered heterocyclyl of R^(a1) are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²; eachR^(b1) is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl and 3- to 8-membered heterocyclyl of R^(b1) are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹²; each R^(c1) and R^(d1) is independently hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl or3- to 8-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl and 3- to 8-memberedheterocyclyl of R^(c1) and R^(d1) are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹²; or R^(c1) andR^(d1) are taken together with the nitrogen atom to which they areattached to form a 4- to 8-membered heterocyclyl optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹²; eachR^(e1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein theC₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryland 3- to 8-membered heterocyclyl of R^(e1) are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹²; each R^(f1) is independently hydrogen or C₁₋₆ alkyl; each R^(g1)and R^(h1) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or —O—C₁₋₆alkyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl and 3- to 8-membered heterocyclyl of R^(g1) andR^(h1) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹²; or R^(g1) and R^(h1) are taken togetherwith the phosphorus atom to which they are attached to form a 4- to8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²; each R^(i1), R^(j1) andR^(k1) is independently C₁₋₆ alkyl; each R¹² is independently oxo, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl, 3- to6-membered heterocyclyl, halogen, cyano,—C(O)R^(a2), —C(O)OR^(b2),—C(O)NR^(c2)R^(d2), —OR^(b2), —OC(O)R^(a2), —OC(O)NR^(c2)R^(d2),—S(O)₂R^(e2), —S(O)₂NR^(c2)R^(d2), —NR^(c2)R^(d2), —N(R^(f2))C(O)R^(a2),—N(R^(f2))C(O)OR^(b2), —N(R^(f2))C(O)NR^(c2)R^(d2),—N(R^(f2))S(O)₂R^(e2), —N(R^(f2))S(O)₂NR^(c2)R^(d2), or—P(O)R^(g2)R^(h2); wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5-to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R¹² areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³; each R^(a2) is independently hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl or 3- to6-membered heterocyclyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl ofR^(a2) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³; each R^(b2) is independently hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl or 3- to 6-membered heterocyclyl; whereinthe C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 3- to 6-membered heterocyclyl ofR^(b2) are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³; each R^(c2) and R^(d2) is independentlyhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or 3- to 8-membered heterocyclyl;wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 3- to 8-memberedheterocyclyl of R^(c2) and R^(d2) are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹³; or R^(c2) andR^(d2) are taken together with the nitrogen atom to which they areattached to form a 4- to 6-membered heterocyclyl optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹³; eachR^(e2) is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to6-membered heteroaryl or 3- to 6-membered heterocyclyl; wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₆ aryl, 5- to 6-membered heteroaryl and 3- to6-membered heterocyclyl of R^(e2) are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹³; each R^(f2)is independently hydrogen or C₁₋₆ alkyl; each R^(g2) and R^(h2) isindependently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3- to 8-memberedheterocyclyl, or —O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and 3- to 8-membered heterocyclyl of R^(g2) and R^(h2) are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³; or R^(g2) and R^(h2) are taken together with thephosphorus atom to which they are attached to form a 4- to 6-memberedheterocyclyl optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹³; and each R¹³ is independently oxo,halogen, hydroxyl, —CKC₁₋₆ alkyl), cyano, C₁₋₆ alkyl or C₁₋₆ haloalkyl;provided that the compound is other than No. Name 2x 2-Pyrrolidinone,1-[3-[[4-[2- (4-amino-2-methylphenoxy)-3-pyridinyl]-2-pyrimidinyl]amino]propyl]-, 3x 4-Morpholinepropanamine, N-[4-[2-(4-amino-2-methylphenoxy)-3-pyridinyl]-2- pyrimidinyl]-, 4x Urea,N-(3-fluoro-4-methylphenyl)-N′-[4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, 5x Urea,N-(2,3-dihydro-1H-inden-5-yl)-N′-[4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, 6x Urea,N-(4-chlorophenyl)-N′-[4-[[3-[2- [[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, 7x Urea,N-[3-methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-N′-[3-(trifluoromethyl)phenyl]-, 8x Urea,N-(5-chloro-2-methoxyphenyl)-N′-[3-methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, or 9x Urea,N-(5-chloro-2-methoxyphenyl)-N′-[3-methyl-4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,

and salts thereof.
 2. The compound of claim 1, wherein R^(2A) and R^(2B)are independently H, F, Cl or C₁-C₆ alkyl.
 3. The compound of claim 2,wherein R^(2A) is H, F or methyl, and R^(2B) is H, F, Cl or —CH₃.
 4. Thecompound of claim 1, wherein R³ is H, F, Cl, —CN, C₁₋₆ alkyl, or C₁₋₆haloalkyl.
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled) 9.The compound of claim 1, wherein R⁵ is H, F, Cl, —CN, C₁₋₆ alkyloptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from R¹⁰, —NR⁸SO₂R⁹, —NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹. 10.The compound of claim 9, wherein R⁵ is C₁₋₄ alkyl substituted with 1, 2,3, 4 or 5 substituents independently selected from R¹⁰, —NR⁸SO₂R⁹,—NR^(8A)R^(8B), or —C(O)N(R⁸)SO₂R⁹.
 11. (canceled)
 12. (canceled) 13.The compound of claim 10, wherein R⁵ is —CH₂NHC(O)-(cyclopropyl),—NHCH₂CH(OH)CF₃, or —C(O)NHSO₂-(2-chlorophenyl).
 14. The compound ofclaim 10, wherein R⁵ is —NHSO₂R⁹, and R⁹ is C₁₋₆ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom R¹⁰, or C₆₋₁₀ aryl optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R¹⁰.
 15. (canceled)
 16. Thecompound of claim 1, wherein R⁴ is —NR⁸C(O)R⁷ or —NR⁸SO₂R⁹. 17.(canceled)
 18. The compound of claim 16, wherein R⁴ is —NH—SO₂R⁹, and R⁹is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, or 5- to 14-memberedheteroaryl, wherein the C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl and 5-to 14-membered heteroaryl of R⁹ are independently optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰. 19.The compound of claim 18, wherein R⁹ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, or 5- to 14-membered heteroaryl, each optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from R¹⁰. 20.(canceled)
 21. (canceled)
 22. (canceled)
 23. The compound of claim 18,wherein R⁹ is selected from the group consisting of cyclopentyl,cyclohexyl, phenyl, 2-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,4-(trifluoromethoxy)phenyl, 3,5-difluorophenyl, 3-pyridyl,1-methyl-1H-imidazol-4-yl, 1-methyl-1H-pyrazol-4-yl, benzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-cyanobenzyl,4-cyanobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,(1-methyl-1H-pyrazol-3-yl)methyl, (5-methylisoxazol-3-yl)methyl,(pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl,cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl,(3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl,(spiro[3.3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, w-propyl, 3-cyano-2,2-dimethylpropyl,3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl,3,3-dimethylbutyl, 3-cyano-3-methylbutyl and 4,4-dimethylpentyl.
 24. Thecompound of claim 16, wherein R⁷ is selected from the group consistingof cyclopropyl, spiro[2.2]pentyl, cyclohexylmethyl and 4-chlorobenzyl.25. The compound of claim 1, wherein R¹ is C₃₋₁₂ cycloalkyl; 3- to14-membered heterocyclyl; —(C₁₋₆ alkylene)-(3- to 14-memberedheterocyclyl), or —(C₁₋₆ alkylene)-NR^(1a)R^(1b); wherein the C₃₋₁₂cycloalkyl, 3- to 14-membered heterocyclyl, and C₁₋₆ alkylene of R¹ areindependently optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from R¹⁰.
 26. (canceled)
 27. (canceled) 28.(canceled)
 29. The compound of claim 25, wherein R¹ is selected from thegroup consisting of piperidin-3-yl, 5-fluoropiperidin-3-yl,5-methylpiperidin-3-yl and 5-fluoro-5-methylpiperidin-3-yl. 30.(canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. The compoundof claim 1, wherein the compound is of the Formula (Ia) or Formula (Ic):

wherein R^(6A) is hydrogen or R⁶; and R¹, R^(2A), R²⁸, R³, R⁵, R⁶ and R⁹are as defined in claim
 1. 35. (canceled)
 36. (canceled)
 37. (canceled)38. (canceled)
 39. The compound of claim 1, wherein the compound is ofthe Formula (Ie):

wherein R^(6A) is hydrogen or R⁶; R²¹ and R²² are independently H, F,—CH₃ or —NH₂, and R^(2A), R^(2B), R³, R⁵, R⁶ and R⁹ are as defined inclaim
 1. 40. The compound of claim 39, wherein the compound is of theFormula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6) or (Ie-7):


41. (canceled)
 42. The compound of claim 1, wherein the compound isselected from the group consisting of

or a pharmaceutically acceptable salt thereof: or

or a pharmaceutically acceptable salt thereof: or

or a pharmaceutically acceptable salt thereof.
 43. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipients.
 44. A method of treating an IRE1-related disease ordisorder, the method comprising administering to a subject having anIRE1-related disease or disorder an effective amount of the compound ofclaim 1, wherein the IRE1-related disease or disorder is cancer. 45.(canceled)
 46. The method of claim 44, wherein the cancer is squamouscell carcinoma, small-cell lung cancer, non-small cell lung cancer(NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneumcancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer,esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer,ovarian cancer, liver cancer, bladder cancer, breast cancer, coloncancer, rectal cancer, colorectal cancer, endometrial cancer, uterinecancer, salivary gland carcinoma, renal cancer, prostate cancer, vulvalcancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma,penile carcinoma, or head and neck cancer.
 47. The method of claim 44,wherein the cancer is lymphoma, lymphocytic leukemia, multiple myeloma(MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), myelodysplastic syndrome (MDS), or myeloproliferative disease(MPD).
 48. The method of claim 44, wherein the cancer is multiplemyeloma or triple-negative breast cancer (TNBC).
 49. (canceled) 50.(canceled)
 51. The method of claim 44, wherein the further comprisingadministering one or more additional therapeutic agents selected fromthe group consisting of a corticosteroid, a proteasome inhibitor, animmunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody,an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-interleukin-6antibody, or a combination thereof.
 52. The method of claim 51, whereinthe corticosteroid comprises dexamethasone: wherein the proteasomeinhibitor comprises carfilzomib, ixazomib or bortezomib; wherein theimmunomodulatory agent comprises lenalidomide or pomalidomide; whereinthe anti-PD-L1 antibody comprises avelumab, durvalumab, or atezolizumab;and wherein the anti-PD-1 antibody comprises pembrolizumab or nivolumab.53.-69. (canceled)